In his club career, which started in 1987, Wilmots played for Sint-Truiden, Mechelen, Standard Liège, Schalke 04, and Bordeaux. At Schalke, he helped them to the 1997 UEFA Cup Final. His goal in the first leg was cancelled out by Internazionale in the second leg, but Schalke went on to win the game on penalties, with Wilmots scoring the decisive goal. He retired in 2003, after his second stint with Schalke. During his time with Schalke, the fans there gave him the affectionate nickname "Das Kampfschwein" (The Warpig), which has been picked up by some English language journalists. In Belgium he is known under the nickname the Bull of Dongelberg, an allusion to his birthplace.
For Belgium, Wilmots scored 28 goals in 70 caps, his first coming in May 1990. He went to four World Cups, playing in three. After being an unused substitute in 1990, he went scoreless in 1994, but scored two goals in 1998 and three in 2002, making him Belgium's leading goal scorer in World Cup history. He also scored a goal against Brazil in the last 16 match of the 2002 World Cup which was disallowed because of a "phantom foul" on Roque Júnior. According to Wilmots, the referee Peter Prendergast apologized for the error to him at half time. Wilmots was named as one of the seven reserves in the 2002 World Cup All-Star Team.
Wilmots became a football manager in summer 2004 for Sint-Truidense, but was sacked in February 2005. Between 2009 and 2012, he served as assistant manager of the Belgium national team under Dick Advocaat and later Georges Leekens. On 15 May 2012, following the exit of Leekens, Wilmots assumed the Belgium reins on an interim basis before going onto become permanent coach, signing a contract until June 2014.
On 11 October 2013, Belgium qualified for the 2014 FIFA World Cup. Wilmots is credited with "not only giving the young group confidence in themselves as well as enjoying a close relationship with his players but also at the same time being capable of instilling discipline to the squad."
After retiring as a footballer, Wilmots went into politics. He was elected to the Senate for the French-speaking liberal party, the Reformist Movement (Mouvement Réformateur or MR) in the 2003 federal election. His political career is not considered very successful. In 2005, he announced that he wanted to resign as a senator, a rather unconventional, and criticized constitutional move.