As a youth, Mertens played for Stade Leuven, Anderlecht and Gent, and made his debut on loan to Eendracht Aalst in the Belgian Third Division. In 2006, he moved to Dutch Eerste Divisie club AGOVV Apeldoorn, where he spent three years before a €600,000 move to Utrecht of the Eredivisie. Two years later he and teammate Kevin Strootman were transferred to PSV Eindhoven for a combined fee of €13 million, and won the KNVB Cup and Johan Cruyff Shield in 2012. In 2013, Mertens signed for Napoli for a €9.6 million fee and has since made over 300 appearances for the club. He won the Coppa Italia and Supercoppa Italiana in 2014, and was named in the Serie A Team of the Year during the 2016–17 season. In 2020, he scored his 122nd goal for the club, surpassing Marek Hamšík as Napoli's all-time top goalscorer.