He played in Major League Baseball (MLB) for the Washington Nationals, Tampa Bay Rays, Arizona Diamondbacks, Chicago Cubs, Los Angeles Dodgers, and Seattle Mariners.

Late in the season, he was benched for breaking team rules, and considered leaving the Nationals' organization to play college football.

In 2013, Souza played for the Harrisburg Senators of the Class AA Eastern League, where he batted .300 with 15 home runs and 20 stolen bases in 77 games.

Souza's performance at the AAA level was recognized with his selection as the International League Most Valuable Player and Rookie of the Year.

[12] In 2015, Souza started the season as an opening day starter, with his first home run as a Ray hitting the hotel in Rogers Centre.

[16] On July 15, Souza set a new career high after hitting his 18th home run of the year into the camera well in Angels Stadium.

Souza was ejected for the first time in his MLB career on May 12, 2018, by home plate umpire Doug Eddings, after throwing his bat in reaction to a called third strike.

[21][22] On May 22, Souza landed on the disabled list for the second time with the same injury, a strained right pectoral muscle, which caused him to miss the first month and a half of the season.

On January 30, 2021, Souza signed a minor league contract with the Houston Astros organization and was invited to Spring Training.

[28] He hit .279 in 22 games with six home runs and 16 RBI for the Triple-A Oklahoma City Dodgers before he was called up to the major leagues on June 16.

[34] Souza was added back to the Dodgers roster for the postseason, and appeared in six games through three different series, primarily as a pinch hitter.

[38] Early in his baseball career, Souza lived a lifestyle characterized by "drinking, staying out late, chasing women.

"[39] After his live-in girlfriend cheated on him with a teammate, and he had a confrontation with Potomac Nationals manager Matt LeCroy, Souza briefly quit baseball in 2011.

[39] Brent Lillibridge, a friend and former major league player, invited him to attend his Christian church outside Seattle.