Contreras signed with the Chicago Cubs as an international free agent in 2009. He made his professional debut with the Dominican Summer League Cubs that year. He batted .205 in 29 games at age 17. In 2010, he batted .313 in 17 games at age 18 with them. In 2011 and 2012 he played with the Boise Hawks. Contreras spent 2013 with the Kane County Cougars, 2014 with the Daytona Cubs and 2015 with the Tennessee Smokies. He was named the Cubs Minor League Player of the Year in 2015 after batting .333/.413/.478 with eight home runs. During his minor league career, he played the positions of catcher, first base, second base, third base, left field, and right field. The Cubs added him to their 40-man roster after the season.

He was promoted to the Cubs major league team on June 17, 2016, playing catcher. On June 19, he hit a two-run home run on the first pitch of his first major-league at-bat after two pick-off attempts by the pitcher to first base, becoming the 30th player in the modern MLB era to do so. In his fifth game, he started at the first base position, and started in left field in his eighth game, establishing himself as a versatile player on the field. Contreras finished the 2016 regular season with 80 hits in 295 at bats with 12 home runs, 35 RBIs and a .275 batting average.

On April 2, 2017, Contreras was the Cubs’ opening day starting catcher against the St. Louis Cardinals. After hitting 5 home runs in 6 games, he was selected as the National League’s Player of the Week on August 8. On August 9, Contreras suffered a moderate hamstring strain while running to first base against the San Francisco Giants. At the time of the injury he was batting .274 with 93 hits in 339 at bats, hit 21 home runs and had 70 RBIs. Willson returned from the injury on September 10 as a pinch hitter. On September 15, 2017, Contreras was ejected and suspended one game for throwing his mask, which bounced and hit umpire Jordan Baker in the shins. In 377 at bats, Contreras finished the season with a .276 batting average, 104 hits, 21 home runs, 5 stolen bases and 74 RBIs.

On October 18, 2017, in Game Four of the NLCS, Contreras hit the longest postseason home run (491 feet) since Statcast started recording such data in 2015.

Batting .287 with seven home runs and 34 RBIs, Contreras was voted to start in the 2018 All-Star Game, his first All-Star appearance. He finished his 2018 campaign batting .249 with ten home runs and 54 RBIs in 138 games.

Contreras’ younger brother, William Contreras, plays for the Atlanta Braves. Contreras married Andrea Villamizar on May 3, 2018.

Contreras had a fast start to the 2019 season, batting .315 with an on-base plus slugging percentage of 1.069 into mid-May. On May 11 he had his first career walk-off hit, a solo shot off the Milwaukee Brewers’ Burch Smith, ending a 15-inning marathon. Contreras and teammate Javier Baez were named starters for the National League in the 2019 All-Star game, but neither registered a hit. On August 3, Contreras strained his hamstring running to first base and was put on the 10-day injured list. He finished the 2019 season slashing .272/.355/.533 with 24 home runs and 64 RBIs over 105 games.