Yanga-Mbiwa joined Montpellier as a youth player in 2005 and made his professional football debut on 23 February 2007 in a 1–0 away defeat to Bastia starting the match and playing the entire 90 minutes, picking up a yellow card. Following the season, he signed his first professional contract agreeing to a three-year deal until 2010. He was officially promoted to the senior squad and was assigned the number 3 shirt. Initially, Yanga-Mbiwa was utilised as a substitute earlier on during the 2007–08 season, but by September 2007, despite being only 18 years old, Montpellier manager Rolland Courbis named Yanga-Mbiwa a starter for the rest of the 2007–08 season. Yanga-Mbiwa didn't disappoint appearing in 41 total matches scoring one goal. Beginning with the club's 31 August 1–0 victory over Ajaccio, Mbiwa appeared in every match Montpellier played including the Coupe de la Ligue and Coupe de France matches, where Montpellier reached the Round of 16 and Round of 32, respectively. His only goal of the season came on 12 May 2008 against FC Gueugnon scoring the winner in injury time to give Montpellier a 2–1 victory. Already established as a regular, Yanga-Mbiwa was an incumbent starter heading into the 2008–09 season, and despite competition from fellow youngsters Mickaël Nelson and Abdel El Kaoutari, he continually impressed appearing in 33 total matches and scoring one goal against Angers in a 3–3 draw again in injury time. The equalising goal came only seconds after Angers took the lead with a goal from Malik Couturier. On 20 March 2009, with Montpellier in a decisive battle for promotion, Yanga-Mbiwa picked up an extensive injury against Brest, which ruled him out for almost two months. He returned to the team on 8 May 2009 and played the final four matches helping Montpellier achieve promotion to Ligue 1 on the final day of the season. Despite promotion to Ligue 1, with his impending stint in prison oncoming, manager Rolland Courbis resigned from his position and new manager René Girard came on. Girard made it clear that one of his many priorities were to keep hold of Yanga-Mbiwa and on 2 June 2009, it was done with the club signing the player to a two-year contract extension until 2012. Yanga-Mbiwa made his Ligue 1 debut in the club's opening match of the season against Paris Saint-Germain playing the entire match in a 1–1 draw. On 12 May 2010, Yanga-Mbiwa added an extra year to his contract after agreeing to a contract extension with the club.
On 22 January 2013, Yanga-Mbiwa completed a transfer to Newcastle United for £8.5 million. He agreed to a five-and-a-half-year deal at St James' Park, where he wore the number 13 shirt. He made his début for Newcastle on 29 January 2013 as a second-half substitute in a 2–1 win against Aston Villa.
On 1 September 2014, Yanga-Mbiwa signed for Italian club Roma on a season-long loan, with an option to make the move permanent for £5.5m on top of the £1m loan fee. He made his debut as a 77th-minute substitute in the Champions League match against CSKA Moscow on 17 September. Four days later, he played in his first Serie A match, starting in a 2–0 win over Cagliari. On 27 January 2015, Newcastle United announced that Yanga-Mbiwa would join Roma on a permanent deal after meeting a contractual condition contained in the loan agreement between the clubs. On 25 May 2015, Yanga-Mbiwa scored his only goal with Roma and the winning goal against club's rival Lazio during the Derby della Capitale in a 2-1 win, which ensured a 2nd-placed finish in the 2014–15 Serie A season as well as earning a start in the 2015–16 UEFA Champions League. He played a total of 38 matches with the "Giallorossi".
On 14 August 2015, Yanga-Mbiwa completed a transfer to French club Lyon for €8 million with possible €2 million bonus fee. On 8 May he scored two to help take Lyon past Monaco, ending his first season with two goals. He terminated his contract with Lyon on the 1st July 2020 with 72 matches played and 2 goals scored for the club in 5 years.
