Born in Feltham, London, Mancienne was spotted by Chelsea as a nine-year-old playing for Kingstonian, and debuted for the Chelsea Reserves while still at school. He signed a professional contract in January 2006, and was called onto the bench for the final match of the 2005–06 season but was unused.

He was part of Chelsea’s pre-season tour of the United States in Summer 2006 and started the season again with a place on the bench; in the 2006 Community Shield against Liverpool and the first two Premier League games of the 2006–07 season against Manchester City and Blackburn Rovers. Despite this, it would be over two years before he would play a competitive game for the Blues, a fact that led him to admit he may need to move on for the sake of his career.

Mancienne gained his first taste of league football in a loan spell at Queens Park Rangers in late 2006, when he joined them for the remainder of the 2006–07 campaign. He played most of his 28 games for the Championship side at right back, but also played a few times in his preferred centre-back position. His impressive displays made him popular with the QPR fans, who voted him runner-up in the Supporters’ Young Player of the Year.

Mancienne is eligible to play for the Seychelles as his father, Michael Snr, originates from there and is a former Seychelles international midfielder. He rejected the chance to play for the Seychelles national team in 2006 in favour of his native England. However, in November 2008, he stated that he would play for Seychelles if he doesn’t get to play for England by the time he reaches 25.

He was an England regular at under-21 level since making his debut against Romania on 21 August 2007. He was part of the side that reached the 2009 European Championships. However, his tournament was a disappointment as he received a red card in their opening group game against Finland.

With no playing opportunities arriving at Stamford Bridge, Mancienne again went out on loan in October 2008 when he joined promotion-chasing Championship side Wolverhampton Wanderers on loan initially until 29 December 2008. His performances during this period caused Wolves to extend his loan by a further month, however, the paperwork on the extension was never completed, and he was recalled by his parent club.

On 15 November 2008, Fabio Capello surprisingly named him in the England squad to play an international friendly match against Germany in Berlin. He did not appear in the game though.

After gaining playing time with spells on loan at Championship sides Queens Park Rangers and Wolverhampton Wanderers, respectively (see below), he finally made his Chelsea debut on 14 February 2009, starting an FA Cup tie at Watford. He made his European debut appearance 11 days later as a late substitute in a UEFA Champions League knock-out tie against Juventus, which ended 1–0 to Chelsea. On 28 February he achieved his Premier League debut in a 2–1 victory over Wigan Athletic.

He signed a new contract with Chelsea in August 2009 that would expire in June 2013.

On 31 May 2011, Mancienne signed a four-year deal at German Bundesliga club Hamburger SV for a fee in the region of £1.752 million. He was reunited with former Chelsea sporting director Frank Arnesen, officially moving on 1 July 2011, when the transfer window opened. He made his debut for the club on 5 August 2011, in a 3–1 defeat at reigning champions Borussia Dortmund.

On 16 July 2014, Mancienne joined Nottingham Forest on a three-year deal, reuniting with his England U21 manager Stuart Pearce. He made his debut against Blackpool on 9 August 2014, starting at centre-half alongside Danny Fox. He played the entire ninety minutes of the 2–0 Forest win, earning the Man of the Match award in the process. Mancienne was then sent off in his second game for the club, following two bookable offences in Forest’s League Cup tie away at Tranmere Rovers on 12 August 2014. Following his suspension, he returned to the side and once again was nominated the fans’ Man of the Match in a 1–0 away win at Sheffield Wednesday.

On 28 April 2017, Mancienne signed a two-year extension to his contract with Nottingham Forest, now managed by Mark Warburton. The contract was signed the day before Mancienne made his 100th appearance in all competitions for the club, in a 2–0 defeat to QPR, and the player reportedly accepted a reduced salary in order to stay at the club.

On 3 August 2018, Mancienne joined Major League Soccer side New England Revolution. His reported salary of $1.28 million in 2018, and $881,676 in 2019, made him not only the highest-paid defender in the league at the time, but also the highest-paid defensive player in the team’s history.