He played in Major League Baseball (MLB) for the Arizona Diamondbacks, Chicago Cubs, Toronto Blue Jays, and Washington Nationals.

[1] Since his arrival in the United States, Montero was coached by veteran manager and former catcher Bill Plummer throughout his time with the Diamondbacks organization.

However, when Snyder was put on the disabled list in June, Montero's playing time increased markedly and he finished the season with a career-high .294 batting average.

[6] During Game 1 of the 2016 NLCS, Montero hit a pinch-hit grand slam in the 8th inning to break a 3–3 tie and led the Cubs to an 8–4 victory over the Los Angeles Dodgers.

Montero entered Game 7 of the 2016 World Series in the bottom of the 9th inning as a defensive replacement for Cubs backup catcher David Ross.

In the top of the 10th inning, having batted only .091 (1-for-11) in the postseason to that point, Montero hit a single to left field which drove in Cubs first baseman Anthony Rizzo and improved the team's lead to 8–6.

After the game, he said that it was the fault of pitcher Jake Arrieta, who took too long to deliver his pitches and failed to hold the runners at their bases.

It was reported this was done because management felt he was a disruption in the clubhouse; Anthony Rizzo considered Montero's comments to the media unprofessional.

[22] Together, in 2017, the couple created the Miguel and Vanessa Montero Foundation, which aims to provide medical assistance to seriously ill children from Venezuela.