Luc Nilis was born in Zonhoven and made his debute in 1984 in the second division for FC Winterslag. In 1986 he was transfered to RSC Anderlecht, where he completed the next 8 seasons. He won four titles (1987, 1991, 1993 and 1994) and three Cups (1988, 1989, 1994).

He scored a lot of goals for the Mauves: three against Grasshoppers Zürich in 1991-1992, HJK Helsinki, Standard de Liège and Germinal Ekeren in 1993-1994. He even managed to score four against Charleroi SC in 1993-1994. Nilis scored with his both feet and had an excellent dribble. Dutch columnist Jan Mulder and Belgian comedian Jacques Vermeire both honoured the player. But he also had a devastating shot. He demonstrated this in the game against KV Mechelen in 1990-1991 and against FC Porto in 1993-1994.

Nilis was never able to win the Golden Shoe and experienced this as a lack of recognition. He left Belgium and went to PSV Eindhoven. He played for 6 years in Holland and won two titles (1997 and 2000) and one Cup (1996). In 1996 he was elected as best player of the year. He also became the best striker in the Dutch league twice.

In the season of 1999-2000, he went to Aston Villa, where he only played three games because of a serious injury. On January 24, 2001 the English club ended his contract and also his carreer.

Nilis was selected many times for the national team, but he never scored many goals. Though he was able to score two goals in the final qualification game against Ireland for the World Cup in France. That way, Belgium was qualified.

After his carreer, Nilis became director of K. Beringen-Heusden-Zolder. Since 2006, he joined PSV Eindhoven's scouting team.