[6] De Vrij made his official debut for Feyenoord's first team on 24 September 2009, when he replaced Kelvin Leerdam in the 58th minute in the KNVB Cup away match against Harkemase Boys (0–5).

However, after a poor run of form in the following campaign, De Vrij was stripped of his armband as it was given first to star striker Graziano Pellè and then to vice-captain Jordy Clasie after the former struggled with disciplinary issues.

[16] In September, he picked up a knee injury on international duty but was passed fit to play a further match for the Netherlands, infuriating Lazio's medical staff.

[20] In March 2018, Lazio's sporting director Igli Tare announced that De Vrij would be leaving the club on a free transfer in the summer.

[27][28] He also made his first UEFA Champions League appearance in season opener against Tottenham Hotspur, assisting Matías Vecino's injury-time winner for a 2–1 home win.

[29] De Vrij eventually played 5 out of 6 matches in the competition's group stage, which saw en early elimination of Inter, instead continuing their European adventure in knockout phase of UEFA Europa League.

[30] Later on 14 March 2019, in the second leg of Europa League round of 16, De Vrij's wrong ball control resulted fatal for Inter who conceded inside 5 minutes, and eventually lost the game to Eintracht Frankfurt 1–0 at San Siro, crashing out of competition 1–0 on aggregate.

[31] Three days later, De Vrij scored in the Derby della Madonnina match against rivals Milan, helping his team to win 3–2,[32] taking back the third place in championship,[33] and completing the first league double over them since 2011–12 season.

[38] De Vrij was paired up with Dico Koppers in central defence[39] and participated in every match the Oranje played without getting substituted, making a notable contribution.

[40] De Vrij was a member of the Netherlands' squad for the 2014 FIFA World Cup,[41] where he scored his first international goal in a 5–1 win over defending champions Spain in the team's opening group match on 13 June.

[43] In the Netherlands' first game of UEFA Euro 2016 qualification away to the Czech Republic on 9 September 2014, De Vrij equalised with a header from Daley Blind's cross but the Dutch lost 2–1.

[44] He headed the team into the lead after 13 minutes in an eventual 2–0 win over Spain in a friendly at the Amsterdam ArenA on 31 March 2015, also wearing the captain's armband after Wesley Sneijder's substitution.

[48] De Vrij was a member of the Dutch squad for the 2022 FIFA World Cup where he was a unused substitute in all five of the team's matches as they were knocked out by eventual winners Argentina at the quarter-final stage.