Born in Neuville-aux-Bois of Réunionnais origin, Plessis started his career at Olympique Lyonnais. Plessis signed for Lyon at the age of 15, and was considered to be one of the team's most promising youngsters, following in the footsteps of Karim Benzema and Hatem Ben Arfa.
Plessis signed a three-year contract for Liverpool on the last day of the transfer window in August 2007. He initially played for the reserve team, with which he won the reserves league in 2008. Liverpool manager Rafael Benítez said of Plessis after having signed him, "He is a good player, big and strong, and we're sure he'll do well for us. He's only a young boy with plenty of time to work on his game but it depends on his progress how quickly he can force his way into the first team". Plessis made his debut for Liverpool on 5 April 2008 in the 1–1 away draw against Arsenal. Rafa Benítez described his performance by saying "Today was the debut for Damien Plessis. We knew when we signed him that he was a quality player. He's played really well for the reserves, and to play as well as he did today in this stadium, it shows we are going in the right direction and in time he will be fighting with the likes of Gerrard and Spearing for a first team place." For the start of the 2008–2009 season Plessis was given the number 28 shirt. He made his debut in the UEFA Champions League during a game against Standard Liege. He also started the first match of the season against Sunderland but only played 45 minutes because of a knock, and fellow midfielder Xabi Alonso came on to replace him. On 23 September 2008, Plessis played in the League Cup game against Crewe Alexandra. He scored his first senior goal for the club in a League Cup match against Tottenham Hotspur on 12 November 2008 when he headed down a corner from Ryan Babel. Plessis signed a two-and-a-half-year extension to his Liverpool contract, in October 2009, that would have kept him at Anfield until 2012. On 12 August 2010, Plessis' shirt number, 28, was taken by new signing Christian Poulsen.
On 31 August 2010, Panathinaikos bought the player from Liverpool on an undisclosed fee. He signed with the club as a promising player, but his performances were below par and never satisfied his manager Jesualdo Ferreira. This way he didn't manage to get much playing time, finishing the season with just 9 appearances for the club. At the end of the season he was expected to leave the club since he was not part of the manager's plans for the following season. In July 2011, Plessis went on trial with Leicester City. However, Sven Goran Eriksson confirmed that the trial was not very successful and quite a short one. He was later rumoured to be in talks with 2. Bundesliga sides Ingolstadt 04 and 1860 Munich. Eventually he didn't reach an agreement with any team and stayed at Panathinaikos.
On 23 December 2011, Doncaster Rovers signed Plessis on loan until the end of the season. He hoped to use the switch as a springboard to winning a move back to the Premier League. However, he never made a first team appearance for the club and was subsequently released in May 2012. On 4 July 2012, Panathinaikos also terminated his contract after two years of sub-par performances for the club.
Arles-Avignon
In July 2012, Plessis joined French Ligue 2 side AC Arles-Avignon on a two-year contract. There he managed to resurrect his foundering career and he became a first team regular.
