Slater made his debut on the wing for Queensland in game one of the 2004 State of Origin series. Slater had a quiet but solid first game in QLD’s 9-8 loss at ANZ Stadium. Slater retained his spot on the team for the second game of the series at Suncorp Stadium. In game two, just days shy of his 21st birthday, Slater was named man of the match after scoring two tries. His second try considered one of the great individual origin tries. Trailing 12–10, Slater latched onto a grubber kick from Darren Lockyer, chip-kicked the ball over Blues fullback Anthony Minichiello, regathering the ball and scoring in QLD’s 22-18 win. Slater scored a try in the decider but could not stop a Brad Fittler inspired New South Wales side from clinching the series in QLD's 36-14 loss. Slater's club form helped his team finish 6th on the ladder, defeating the Brisbane Broncos 31-14 at Suncorp Stadium in the first game of the finals before succumbing to eventual premiers, the Canterbury-Bankstown Bulldogs 43-18 at SFS. Slater played 22 matches and scored 14 tries for the Storm in the 2004 NRL season. Following his stellar season, Slater was named in the Kangaroo squad to tour Europe but injury prevented him from joining in the tour.
Slater once again impressed in his third NRL season. Once again Slater was picked for the Queensland State of Origin team, this time at his preferred position of fullback. Slater returned for the second game in Sydney which saw the return of Andrew Johns, who spearheaded a New South Wales victory. Despite losing the match 32-22, Slater took advantage of a knock-on from the Blues Anthony Minichiello to score a length of the field try during the match. Slater was dumped from the Queensland side for the deciding third game in Brisbane which led to outrage from some Maroons fans. With injuries and suspensions, Slater had to wait three years for another chance at State of Origin. Slater continued his brilliant form throughout 2005, topping the try scoring charts with 20 tries in 21 matches for the Storm. Melbourne once again finished 6th in the league and defeated the Brisbane Broncos 24-18 at Suncorp Stadium in the first game of the finals before missing the Storms 24-16 season ending loss succumbing to an in-form North Queensland Cowboys team at SFS.
Slater had a less successful 2006 season. Slater was suspended in Round 4 for seven matches for kicking Wests Tigers prop John Skandalis in the Storms’ 30-28 loss at Leichhardt Oval, Slater also scored two tries in the match. Injuries and suspensions kept Slater out of contention for a spot in the Queensland team in 2006 and Karmichael Hunt would cement his place as the Queensland fullback. In his comeback game in Round 13 against the Sydney Roosters in the Storms 20-16 win at Olympic Park, Slater only played 25 minutes of the second half on the wing and was later found guilty of using a dangerous throw on Roosters centre Ryan Cross. Slater was suspended for 2 matches. After Slater's second suspension, Melbourne Storm coach Craig Bellamy decided to give Slater some warm up matches for his comeback into first grade with both North Sydney Bears (Melbourne's feeder club in the NSWRL Premier League) and Norths Devils (Melbourne's feeder club in the Queensland Cup). Slater made his NRL comeback in Round 18 playing his preferred fullback position when the Storm defeated the Brisbane Broncos 10-4 at Olympic Park. In Round 22 against the Wests Tigers in the Storms 46-4 win at Olympic Park, Slater was given a two match suspension for a late forearm, which was his third suspension for the season. Slater came back to the main line-up in Round 25 against the Canberra Raiders in the Storms 22-18 win at Canberra Stadium. A few weeks later, after having claimed the minor premiership the Storm again met the Brisbane Broncos, this time in the 2006 NRL Grand Final. It was Slater's first and he played at fullback in what was Melbourne's first grand final loss after succumbing 15-8 to a Darren Lockyer inspired Broncos team in Melbourne player Scott Hill farewell NRL match before moving to the ESL and the Broncos prop legend Shane Webcke farewell into retirement. Slater played in 15 matches and scored 5 tries for the Storm in the 2006 NRL season.
Slater's start to the 2008 season can be described as nothing short of sensational. He scored 3 tries in Melbourne's 32–18 Round 1 win at Etihad Stadium, one at SFS in Round 3, a 10–6 loss to the Sydney Roosters and two at Olympic Park in Melbourne's 26–4 win over the Manly-Warringah Sea Eagles. After his start to the season, Slater garnered praise from league experts such as Laurie Daley and Andrew Johns as being the best player in the game. Slater's form was rewarded when he was selected at fullback for the Australian national team in the Centenary Test against New Zealand, displacing the incumbent Brett Stewart. Slater had a modest game in attack for Australia but proved his worth by making numerous try-saving tackles in Australia's 28–12 victory at SCG. Two weeks later, Slater was selected to once again represent Queensland in the 2008 State of Origin series, this time displacing incumbent, Karmichael Hunt from fullback to five-eighth, Slater had a mixed performance for Queensland throwing a few loose passes despite running over 220 metres and making a line break that nearly resulted in a try to Greg Inglis. Queensland eventually lost, 18–10. Slater returned for Game 2 but was dropped to the interchange bench before replacing Karmichael Hunt 30 minutes into the match at ANZ Stadium. In Game 2 Slater played off the interchange bench in QLD’s 30-0 win in Brisbane. In Game 3, Slater once again started from the interchange bench with Karmichael Hunt starting at fullback. A broken arm to Scott Prince at the 17-minute mark forced Slater to fullback with Karmichael Hunt switching to five eighth. Slater broke the line with his first touch and kick return of the game. He was excellent under the high ball, thwarting many attacking kicks. With just 10 minutes to go, Johnathan Thurston broke the New South Wales line, drawing in the fullback before passing the ball to Slater who ran the remaining 30 metres to score the match-winning try and a 16–10 victory. It was Slater's first series win for Queensland. In Round 19, Slater was involved in an all-in brawl in a match against the St George Illawarra Dragons in the Storms 26-0 win at Olympic Park. He was sin-binned for throwing several punches at winger, Jason Nightingale. He had a two-match suspension downgraded to one match after claiming Nightingale had provoked him with several head-butts throughout the match. In August 2008, Slater was named in the preliminary 46-man Kangaroos squad for the 2008 World Cup. In September 2008; Slater narrowly missed out on the Dally M Medal, Player of the Year, finishing 2 points behind the Sea EaglesMatt Orford. The one-week suspension in Round 19 deducted 3 points from Slater's tally, which would have won him the medal. Days after playing in the 2008 NRL Grand Final 40-0 defeat the Manly-Warringah Sea Eagles, Slater was named the Melbourne club's Player of the Year. Slater played in 24 matches and scored 14 tries for the Storm in the 2008 NRL season. Slater capped off a brilliant year by winning the Rugby League World Golden Boot Award as the best player in the world. In 2008 he also received the Rugby League International Federation's international player of the year award. In October 2008 Slater was selected in the final 24-man Australian squad but hesitated playing since he and his wife were expecting their first child. Slater went on to play fullback for Australia in the 2008 World Cup, scoring hat-tricks in matches against England (52-4 win at Etihad) & Fiji (52-0 win at SFS). Billy Slater won the Man of the match twice in tournament for his performance in both games. About midway through the second half of the World Cup final Slater, who had set up Australia's first two tries, made a grave misjudgement, Slater threw a wild pass back in field after attempting to go the short side from a kick return and it was snapped up by Benji Marshall for a gift four-pointer. Although Melbourne teammate Greg Inglis bought them back within 2 points with a try, a penalty try, courtesy of a Joel Monaghan infringement, ruled out any possible comeback. Although Australia lost the game 34-20 to New Zealand, Slater was named Player of the Tournament following the World Cup final in Brisbane. Slater was also the competition's top tryscorer with 7 tries.
Slater was selected for Australia in the 2009 ANZAC Test match at fullback against New Zealand at Suncorp Stadium in the Kangaroos 38-10 redemption win over the Kiwis. In April 2009, he was named in the preliminary 25-man squad to represent Queensland in the opening State of Origin match for 2009, and was subsequently picked at fullback for the opening State of Origin match. Slater was the first try scorer in the 2009 State of Origin Series scoring in Queensland’s 28-18 win in Sydney. Slater played in the other 2 matches in the Queensland's 2009 winning State of Origin team. In Round 22 against the North Queensland Cowboys at Olympic Park, Slater played 150th NRL career match in the Storms 20-8 win. Melbourne finished the season 4th on the NRL table and avenged their 2008 Grand Final loss to Manly by defeating them 40–12 in the first week of the finals at Etihad Stadium. Slater's four try haul earned him man of the match honours. Slater notched up his 100th NRL career try in Melbourne's 40–10 defeat of the Brisbane Broncos in the preliminary final at Etihad Stadium, becoming only the second Melbourne player to do so after Matt Geyer. In the next week, the Grand Final was won by the Melbourne Storm over the Parramatta Eels 23–16. Slater scored a try and was judged best on ground, earning the Clive Churchill Medal. Slater was named the Storms highest tryscorer in the 2009 NRL season with 18 tries in 26 matches. The following week Slater was named Melbourne's Player of the Year making it the second consecutive year he won the award. During the off-season he was given the first 'Player of the Finals' award, presented by the Rugby League Writers' Association. Slater topped off the season with selection for Australia in the 2009 Four Nations tournament in Europe. Slater played in the first two matches against New Zealand and then England. Slater scored three tries in Australia's 46–16 win over England in the final and also acrobatically tapped the ball back infield setting up a try for teammate, Cameron Smith.
For the 2010 ANZAC Test, Slater was selected to play for Australia at fullback in their 12-8 victory against New Zealand at AAMI Park. Despite Melbourne being stripped of their 2007 and 2009 premierships due to the discovery of a salary cap breach, Slater was allowed to keep his Clive Churchill Medal. Slater was also involved in Queensland's 3–0 whitewash in the 2010 State of Origin series and received the Wally Lewis Medal for player of the series. In the third match, he saved a certain try, before scoring the match-turning and winning try with five minutes remaining in Queensland’s 23-18 win in Sydney. Slater played in 22 matches and scored 10 tries in the Storms drama filled 2010 NRL season. In the post season, Slater was included in the Australian2010 Four Nations squad. Slater scored 3 tries in 3 matches, including scoring a try in the Kangaroos 16-12 Four Nations Final match loss to New Zealand at Suncorp Stadium.
An established ambassador for Adidas, in 2012 Slater appeared as part of a promotional campaign for their F50 adizero III boots alongside Dale Thomas of Aussie Rules and European football (soccer) player David Villa