Guarín was born in Puerto Boyacá. In 2005, already a regular for Envigado F.C. and the Colombian under-20 national team, he was taken on loan by Boca Juniors in the Argentine Primera División, where he spent the first six months in the youth team; upon completion of his loan the Buenos Aires-based club attempted to sign him on a permanent basis, but he instead chose to go on loan to AS Saint-Étienne in August 2006.

Guarín made his debut for the French side scoring twice in a friendly against RCD Espanyol, and gradually fought his way into the starting lineup as the season closed. He first appeared in the Ligue 1 on 14 October 2006 against Olympique Lyonnais, and scored his first goal in a 3–1 victory over Troyes AC; in April 2007, the deal was made permanent for four years.

On 24 May 2006, Guarín made his international debut for Colombia, in a pre-World Cup friendly against Ecuador. He represented the nation at the 2005 CONCACAF Gold Cup and the 2011 Copa América.

On 10 July 2008, Guarín penned a four-year deal with Primeira Liga club FC Porto for an undisclosed fee. Portuguese under-21 international Paulo Machado went the opposite direction, on loan. During his spell he was used mainly as a substitute, but managed to appear regularly; arguably, his most important goal came on 16 May 2010 as the team renewed their Taça de Portugal title, defeating G.D. Chaves 2–1.

On 31 January 2012, Guarín joined Inter Milan for €1.5 million, on loan, with the player replacing Paris Saint-Germain FC-bound Thiago Motta. The Italians also had an option to make the move permanent for €13.5 million in June.

On 17 May 2012, Inter made the move permanent but for €11 million. Guarín scored his first official goal for the Nerazzurri on 30 August, in a 2–2 home draw against FC Vaslui in the Europa League (4–2 on aggregate). In the group stage of the same competition, he provided all three assists in a 3–1 defeat of Neftchi Baku PFC.

Again in the Europa League, on 21 February 2013, Guarín scored twice in a 3–0 away win over CFR Cluj (5–0 on aggregate) to help Inter make it through to the last 16. In the January 2014 transfer window, he was supposed to move to Juventus F.C. in exchange for Mirko Vučinić, but the deal ultimately fell through after the clubs could not reach an agreement. He declared he would not return to the Nerazzurri if he was not allowed to leave, but eventually he reconsidered; it was later reported that he simply wanted to clarify his future with the club, stating that he never asked to leave and that he was confused as to why the situation was created.

In 2013, Guarín’s Inter manager Andrea Stramaccioni described him as “…an extraordinary player who combines physicality with technique in an incredible way. He is also an important element in the locker room.”

On 25 March 2014, Guarín agreed to extend his contract with Inter until 2017. On 14 September, as a second-half substitute, he scored in a 7–0 home win against U.S. Sassuolo Calcio. At the start of the 2014–15 season, he began being used by manager Walter Mazzarri as a second striker.

On 7 December 2014, in his 100th appearance for Inter, Guarín assisted Mauro Icardi in the 44th minute of an eventual 1–2 home defeat against Udinese Calcio. On 16 February of the following year, he scored twice after winning a first-minute penalty kick in a 4–1 success at Atalanta BC, helping his team to secure the first away win in the league since December 2014.

On 10 May 2015, whilst at the service of Inter, Guarín suffered a muscular injury to his right leg, being ruled out of the Copa América.

On 26 January 2016, Guarín joined Shanghai Greenland Shenhua F.C. in the Chinese Super League for a reported €11 million fee plus bonuses. On 26 September 2019, the 33-year-old free agent moved to the Campeonato Brasileiro Série A with CR Vasco da Gama.