He has previously played in Major League Baseball (MLB) for the Houston Astros, Milwaukee Brewers, Seattle Mariners, and Cleveland Indians.

The next year, he split the season between the Low-A Williamsport Crosscutters and the Single-A Lakewood BlueClaws, batting a cumulative .211/.329/.333 with 8 home runs and 36 RBI.

[2] The Phillies traded Santana to the Houston Astros on July 31, 2011, with Jon Singleton, Jarred Cosart, and Josh Zeid, in exchange for Hunter Pence.

He spent the 2013 season with the Double-A Corpus Christi Hooks, posting a .252/.345/.498 slash line with a career-high 25 home runs and 64 RBI.

[9] On July 30, 2015, the Astros traded Santana, Brett Phillips, Josh Hader, and Adrian Houser to the Milwaukee Brewers for Carlos Gómez and Mike Fiers.

[10] The Brewers assigned Santana to the Colorado Springs Sky Sox of the PCL, and promoted him to the major leagues on August 21.

On July 26, 2017, Santana hit the longest home run in the history of Nationals Park, a 475-foot (145 m) shot which landed on the concourse behind the left field stands.

Santana continued as the starting right fielder for the remainder of the season, finishing with 30 home runs and 85 RBIs in 151 games.

[23] Santana was designated for assignment by the Indians on August 31, after he struggled to a .157/.298/.286 slash line with two home runs and 12 RBI in 24 games.