Goddard was selected by St Kilda with the first pick in the 2002 AFL Draft. He debuted in the 2003 season while completing his VCE as a Year 12 student at Caulfield Grammar School. He played in St Kilda’s 2004 Wizard Home Loans Cup winning side – the club's second pre-season cup win. As a Number 1 draft pick, Goddard came under a lot of criticism in his early years.
In 2007, during the Saints' Round 7 game against the Sydney Swans, Goddard fell hard on his left knee which resulted in a ruptured ACL. The injury ended his season.
Goddard returned to play in Round 3 in 2008 and produced a solid season thereafter. He signed on to stay with St Kilda until 2010, despite attempts by other clubs to recruit him.
After the first few rounds of the 2009 season, Goddard was noted as one of the stronger players in the league and became an early favourite for the Brownlow Medal.
Although Goddard is generally a backman and midfielder, in Round 3 he was positioned in an irregular position at full forward and kicked four goals in the first quarter, the most he had ever kicked in a single game until that time. He did not kick another goal for the game but gained 28 disposals in a best on field game.
Goddard played in 21 of 22 matches in the 2009 season home and away rounds in which St Kilda qualified in first position for the finals series, winning the club’s third minor premiership.
Goddard averaged 27.2 possessions per game in 24 matches in 2009 and was recognised for his excellent season with selection in the 2009 All-Australian Team as an interchange player. This was his first career All-Australian Team award.
St Kilda qualified for the 2009 AFL Grand Final after qualifying and preliminary finals wins. Goddard played in the grand final in which St Kilda were defeated by 12 points.
At the conclusion of the 2009 season, Goddard finished as runner-up for the Trevor Barker Award, the award for the best and fairest St Kilda player during the home and away season.
Goddard played 25 games in 2010 (including four finals matches) and averaged 28.7 possessions. He was rewarded with All-Australian selection and finished third in St Kilda's best and fairest award (Trevor Barker Medal). Goddard received 14 votes in the 2010 Brownlow Medal, going into the night as one of the favourites to win.
In the drawn 2010 AFL Grand Final, Goddard finished second in the voting for the Norm Smith Medal, with seven votes. His teammate Lenny Hayes won the Norm Smith Medal with 13 votes. Goddard signed until the end of the 2012 season.
On 1 October 2012, Goddard signed with Essendon and became the first big names to use the AFL's new free-agency period which debuted in 2012. Goddard had refused to sign a new three-year deal all season and instead opted to sign with the Bombers, who offered him higher pay and a four-year contract. Goddard was formally offered the deal by Essendon at 11am on 1 October, with St Kilda allowed 72-hours in which to make a counter offer. However, the Saints decided by the end of the day that they were not willing to match the offer, therefore allowing Goddard to join the Bombers. In making a formal statement of the decision, St Kilda head of football, Chris Pelchen, stipulated that the club had made a significant offer to Goddard "that was relative to both his position and other players within the team. While we are disappointed at his decision to leave the Saints, we are absolutely committed to our ‘team first’ philosophy in relation to player contracts." St Kilda's senior coach, Scott Watters, further elaborated on the reasons St Kilda chose not to counter the Bombers' offer: "As far as the offer that was put forward to Brendon, it would've put him in the top two highest paid players at our football club", Watters said. "The reason (for Goddard leaving) is money. It's that simple." St Kilda was said to have offered "significantly more" than $500,000 a year to Goddard.
Joining Essendon with aspirations of winning a premiership, Goddard found himself walking into one of the biggest controversies in Australian sporting history. Goddard took on the responsibility of being a leader and speaking to the media where his new teammates were not allowed to speak. On top of this, his onfield performances were fantastic. Goddard’s terrific first season at Essendon was capped off when he won the Crichton Medal, the first best and fairest of his career. Goddard played every game, mainly through the midfield, and averaged 26 disposals. He also kicked 18 goals, his best season tally since 2010. Goddard’s leadership continued to be valued on and off the field and his maturity and experience in big games proved invaluable to the young Bomber list.
In 2014 Goddard once again maintained his fantastic form on the field, whilst again being a voice for his teammates in the media. Goddard was important in Essendon's loss to North Melbourne Football Club and finished the year third in Essendon's best and fairest.
In January 2016, Goddard was named as Essendon's captain, replacing the suspendedJobe Watson, Mark Baguley was named as vice captain.