Mignolet started his career with Belgian Second Division side Sint-Truiden in 2004, and spent six years with the club, making 100 senior league appearances and scoring a goal.

He first joined his local football team, Belgian Second Division side Sint-Truiden, in 2004, eventually rising through their youth system to become their first-choice goalkeeper in 2006 at age 18 after the departure of Dušan Belić.

After being invited for a training ground tour, Mignolet signed a five-year contract with English Premier League club Sunderland on 17 June 2010 in a deal worth £2 million.

In the next home match, a 1–0 victory against Manchester City, Mignolet kept his first clean sheet for Sunderland, following an excellent reaction save to deny Emmanuel Adebayor a goal.

Mignolet did not feature again until 8 January 2011, when Sunderland suffered a loss at home to Notts County in the third round of the FA Cup.

Mignolet would become first-choice goalkeeper again after a knee injury to Gordon in February, and earned a string of rave reviews for his performances.

[citation needed] Following the draw, Sunderland manager Steve Bruce hailed the young goalkeeper's fine start to life in English football.

[10] On 29 October 2011, Mignolet was injured during a 2–2 draw with Aston Villa, suffering a broken nose following a collision with Emile Heskey.

Two weeks later, he conceded his first goals for Liverpool in the Premier League in a 2–2 draw with Swansea City, though he was still named man of the match for the fixture.

[19] After this match, Mignolet kept four consecutive clean sheets against Sunderland, Aston Villa, West Ham United and Everton respectively.

[21] On 16 March, Mignolet continued his resurgence in a 1–0 victory against Swansea City, keeping a clean sheet as part of a strong performance.

[29] On 26 December, Mignolet and teammate Philippe Coutinho both made their 200th appearances for Liverpool in a 5–0 Premier League win over Swansea City.

[30] Liverpool signed Alisson Becker[31] as their first choice goalkeeper which led to Mignolet playing domestic cup games only.

[33] On 4 August 2019, following the 2019 FA Community Shield, Mignolet signed a five-year contract with Belgian side Club Brugge, for a reported fee of £6.4 million.