Murphy impressed pundits in his first season, and he was an early favourite for the NAB AFL Rising Star Award. In July, Murphy sustained a season-ending shoulder injury; this effectively ended any chance he had of winning the Rising Star Award, however he was still voted by his peers the winner of the AFLPABest First Year Player award. He led the Carlton Football Club in assists for the season, despite playing only twelve full games.
Murphy was elevated to the eight-man leadership group for the 2007 season. In early 2007 Murphy replicated his good form of 2006, amassing 30 disposals against eventual premiers Geelong in Round 2. However, an injury to prime midfielder Nick Stevens after Round 3 saw Murphy attract the opposition's best taggers in most games. While his form remained solid, shaking the experienced taggers proved too big a challenge for the second year player and he finished outside the top 10 in the club's best and fairest.
Murphy added considerable bulk to his frame during the 2007/08 offseason, highlighted in many preseason news articles. He was no longer in the leadership group, which was now reduced five players. Murphy benefitted significantly from the return of Nick Stevens and the recruitment of Chris Judd, the pair of whom now attracted the strongest taggers, and this gave him more freedom to run. A solid 32 touches against Brisbane in Round 8, then having a game breaking 33 touches against Port Adelaide in Round 11 with the Blues getting home by 12 points after trailing by as much as 38 points in the 3rd quarter. He played his 50th game in round 15 against the Saints. Murphy capped off a great 2008 season by coming second to Chris Judd in the John Nicholls Medal for the Carlton Best and Fairest, recording 11 votes in the Brownlow Medal.
Marc Murphy was selected for Australia in the International Rules series against Ireland. He was one of Australia's best in the first test, kicking 4 overs to assist a late-game comeback by Australia which fell one point short. He scored a goal in the second test by unintentionally tapping the ball into the net from crowded contest.
Murphy continued to improve in the 2009 season, establishing himself as one of the elite midfielders in the AFL, and averaging 25.6 disposals per game. He became Carlton's most potent goal-scoring midfielder, setting himself a personal target of averaging a goal a game, and he achieved this with a total of 31 goals from his 23 matches. After becoming a damaging midfielder, he was selected in the All-Australian Squad of 40, but was not selected in the team, and polled 15 Brownlow Medal votes to finish equal 9th. He again finished second in the Best and Fairest award (John Nicholls Medal) behind his captain Chris Judd.
Murphy played his 100th game in Round 21, 2010; in doing so, he, father John (275 games for Fitzroy, South Melbourne and North Melbourne), and grandfather Leo Murphy (132 games for Hawthorn) became the only father-son-grandson combination in league history to each play 100 games.
Murphy missed much of the 2010 pre-season due to hip surgery, and struggled through the first half of the year. However, his second half of the season was exemplary, polling best and fairest votes in every game after Round 14 and ultimately finishing third for the award.
Murphy became one of the league's elite midfielders in 2011. He was named in the All-Australian team for the first time in his career, on the half-forward flank, and won his first John Nicholls Medal for best and fairest player at Carlton. He was also named as the AFL Coaches' Association Champion Player of the Year, and The Age' Player of the Year.
Murphy started the year as strong as he finished 2011, becoming the favourite for the Brownlow Medal before a heavy collision with Patrick Dangerfield in round 8 where he sustained a shoulder injury. He returned in round 16, and from round 17 to 21 was named as the acting captain in the absence of Chris Judd.