Bacca began his professional career with Atlético Junior in 2006, where he did not have many chances to play. While playing football, Bacca had a second job working as a bus driver’s assistant, to earn more money since his family came from a poor background. On loan at Barranquilla FC in 2007, Bacca made 27 appearances and scored 12 goals. After that, he joined Venezuelan club Minervén on loan for a season. Bacca led the club into second place in the league, scoring 12 goals in 29 games. In 2008, Bacca rejoined Barranquilla on loan once again and was the league top scorer with 14 goals in 19 games.

In his first professional season at Junior, Bacca quickly earned himself a regular first team place and was the top scorer in the 2009 Copa Colombia. One year later, in 2010, he became the winner and top goalscorer of the Categoría Primera A, repeating in 2011 as winner and top goalscorer giving Junior their sixth and seventh Colombian titles.

Bacca scored his first goal for the senior national team in his debut on 11 August 2010, putting Colombia in front against Bolivia at the Estadio Hernando Siles in La Paz; the match finished in a 1–1 draw. His next goal for Colombia came over two years later, scoring his side’s second of the match in a 3–0 win over Cameroon on 17 October 2012.

He made his debut on 21 January 2012, coming on as a substitute for Lior Refaelov in the 68th minute, as Brugge lost 1–0 against Mechelen. In his first three months at Brugge, Bacca struggled to make a breakthrough in the first team, but in the playoffs, he earned his place in the first team. On 15 April 2012, Bacca scored his first league goal for the club against Gent, which gave Brugge the 1–0 win. Then in the last game of the season, Bacca scored twice, in a 3–2 win over Kortrijk, as Brugge finished in second place to earn a European spot.

At the start of the 2012–13 season, Bacca started to play more regularly after the departure of Joseph Akpala and earned the trust of new manager Georges Leekens. In January 2013, having scored 18 goals to date, Bacca asked for a transfer after announcing his intention to leave Brugge. This in response to several clubs throughout Europe expressing an interest in Bacca. However, in an unexpected turn of events two weeks later, Bacca signed a new contract that would have kept him at the club until 2016. At the end of the 2012–13 season, Bacca finished as the league’s top scorer. This led to him being nominated for the Player of the Year in Belgium. Six days later, Bacca won the award in Belgium and wrote on Twitter saying, “Thanks to my family, friends, family and Club Brugge especially throughout Colombia, this award is for you, thanks for your support.”

On 9 July 2013, Spanish club Sevilla signed Bacca for €7 million on a five-year contract with a €30 million buy-out release clause.

On 26 March 2014, Bacca netted two goals in a 2–1 Sevilla victory against the then league leaders Real Madrid at the Ramón Sánchez Pizjuán Stadium. In the second leg of Sevilla’s Europa League quarter-final tie with Porto on 10 April, he scored his side’s third goal in a 4–1 win, securing a 4–2 aggregate victory and a spot in the semi-finals of the competition. Two weeks later, he scored the second goal in their 2–0 semi-final first leg win over compatriots Valencia. In the final on 14 May, he scored in the penalty shootout where Sevilla beat Benfica to lift the trophy. Bacca was voted by Marca as the best signing of the 2013–14 La Liga season. At the LFP Awards, he was voted the season’s best player from the Americas, ahead of Real Madrid’s Ángel Di María and Barcelona’s Neymar.

On 30 September 2014, Bacca signed a contract extension with Sevilla, keeping him at the club until 2018. He scored seven European goals as the club retained their Europa League crown, including two in the final for a 3–2 victory over Dnipro Dnipropetrovsk, thus qualifying the team to the next season’s Champions League.

On 31 May 2014, Bacca scored to put Colombia ahead 2–0 against Senegal, in a match that finished 2–2. Bacca was selected to the final 23-man roster for Colombia at the 2014 FIFA World Cup in Brazil less than a week later. Bacca made one appearance in the finals, coming on as a substitute and winning a penalty in Colombia’s 1–2 defeat to hosts Brazil in the quarter-finals.

In a friendly match against El Salvador at the Red Bull Arena in Harrison, New Jersey on 10 October 2014, Bacca scored twice as Colombia won 3–0.

On 2 July 2015, Serie A club Milan announced the signing of Bacca after activating his buyout clause of reported €30 million, subject to a medical. He made his debut for Milan in a friendly win over city rivals Internazionale in Shenzhen, China. He made his competitive debut on 17 August in the third round of the Coppa Italia, starting in a 2–0 win over Perugia at the San Siro. He scored his first goal in Serie A on 29 August 2015 in a 2–1 home win against Empoli. He scored his first brace in Serie A on 19 September in a 3–2 home win against Palermo. On 13 January 2016, he scored a rabona-style goal against Carpi in a 2–1 Coppa Italia win, taking Milan to the semi-finals of the tournament, then scored again in the weekend as Milan beat Fiorentina 2–0. On 31 January, he scored in the Derby della Madonnina against Inter, helping Milan triumph 3–0, then again three days later in a 2–0 victory at Palermo. On 21 August 2016 he scored his first hat-trick against Torino in a 3–2 win at San Siro.

In May 2015, Bacca was included in Colombia’s 23-man squad for the 2015 Copa América by coach José Pékerman. After the team’s second match, a 1–0 win against Brazil in Santiago on 17 June, Bacca was red carded after the final whistle for pushing over Brazilian striker Neymar, who himself was earlier sent off for deliberately kicking the ball at Pablo Armero. Bacca was given a two-match ban, while Neymar was suspended for four matches.

On 25 June 2016, Bacca scored Colombia’s match-winning goal against hosts the United States in a 1–0 win in the third-place match of the Copa América Centenario.

On 16 August 2017, Villarreal confirmed the signing of Bacca on a one-year loan deal for a fee of €2.5 million, with the option to purchase the player for an additional €15.5 million. Four days later he made his debut in the first game of the new season, starting in a 1–0 loss at Levante alongside fellow debutant Enes Ünal. He scored his first goal for the Yellow Submarine on 10 September, capitalising on an error by Real Betis goalkeeper Antonio Adán to open a 3–1 win at the Estadio de la Cerámica.

On 17 August 2018, Bacca was sold to Villarreal as part of a transaction for Samu Castillejo.

In May 2018 he was named in Colombia’s 23-man squad for the 2018 FIFA World Cup in Russia. At the finals, he missed in the penalty shootout as Colombia went out at the Round of 16 stage to England.