Nainggolan began playing football with Tubantia Borgerhout at the age of 5. Seven years later he moved to the youth team of Germinal Beerschot, where he remained until 2005, when he was noted by Alessandro Beltrami and moved to Italian Serie B club Piacenza. He made his senior debut on 28 May 2006, during a home defeat to Arezzo, being inserted permanently into the first team the following season.

Nainggolan earned his first senior cap on 29 May 2009, against Chile in the Kirin Cup. He scored his first goal for the Red Devils on 5 March 2014, in a 2–2 friendly draw with Côte d’Ivoire.

Nainggolan’s mother died in 2010, and after her death he tattooed two large wings on his back with her dates of birth and death. He was raised Roman Catholic and spoke Dutch, English, French and Italian fluently.

On 27 January 2010, Nainggolan was loaned to Cagliari with a buyout clause. He made his Serie A debut on 7 February, playing seven minutes in a 0–3 away loss against Inter Milan. After making seven appearances (including being sent off a few minutes after entering the field on 28 February against Chievo Verona), the club announced it had acquired 50% of his rights in a co-ownership deal.

In the first part of 2010–11, under manager Pierpaolo Bisoli, Nainggolan started often due to the absence of Daniele Conti. On 31 October 2010 he scored his first goal in the Italian top level, from a right-footed volley in a 2–0 home win over Bologna. On 31 January 2011, Cagliari redeemed the second half of his contract from Piacenza.

On 7 January 2014, Nainggolan was loaned to fellow league team Roma until the end of the campaign for a fee of €3 million, with an option to purchase 50% of his rights in the ensuing summer for €6 million. He made his debut two days later, starting in a 1–0 home win over Sampdoria for the Coppa Italia which qualified to the quarter-finals. In the same competition, he also helped dispose of Juventus in said stage by playing the full 90 minutes 12 days later.

On 22 February 2014, Nainggolan scored his first goal for the capital side, grabbing the 1–0 winner against Bologna. His second, which arrived on 19 April against Fiorentina (same result) ensured his team automatic qualification to the UEFA Champions League.

On 13 May 2014, Nainggolan was selected in a standby list for the 2014 FIFA World Cup. He did not make the final cut, however.

Nainggolan signed a permanent deal with Roma in the 2015 off-season, for €9 million. On 6 July of the following year he renewed his contract until June 2020, extending it a further year the following summer.

On 26 August 2017, aged 29, Nainggolan announced that he would be retiring from international football after not being selected for Belgium’s upcoming World Cup qualifiers, and stated that he would be focusing on his club career with Roma. However, he was selected by new manager Roberto Martínez for friendlies against Mexico and Japan in November, only to pull out due to injury.

On 26 June 2018, Nainggolan signed with Inter Milan for €38 million (€24 million plus Davide Santon and Nicolò Zaniolo, valued at €14 million) until June 2022. He scored in his league debut on 1 September, helping the visitors defeat Bologna 3–0, and just over a month later he netted the equaliser in a 2–1 comeback win at PSV Eindhoven in the Champions League group stage to become the first-ever Belgian to score for the club in the competition.

On 21 May 2018, after once again not being picked for the upcoming World Cup in Russia, Nainggolan retired from the international scene.

In August 2019, Nainggolan returned to Cagliari on a season-long loan. He was named the league’s MVP for November, with two long-range goals and three assists in three matches to help his team reach fourth place.

On 10 July 2019, Lai confirmed in an Instagram post that she had been diagnosed with cancer and would begin chemotherapy treatment. On 8 October 2020, it was announced that Nainggolan tested positive for COVID-19 amid its pandemic in Italy.