He played in Major League Baseball (MLB) for the Milwaukee Brewers, Cincinnati Reds, and San Francisco Giants.

Gennett collected his first major league hit, a single to right-center, in the bottom of the ninth inning, off of pitcher Jesse Chavez, on June 5.

[6] Gennett did well against right-handed pitching, but keeping with what became problematic for him as he moved up through the minors, he struggled against same-handed opponents with only four hits and one walk in 37 plate appearances versus lefties through the All-Star Break.

[11] On April 3, 2017, Gennett hit a two-out, two-run home run in the bottom of the ninth on Opening Day against the Philadelphia Phillies.

[12] On June 6, 2017, Gennett hit a record-tying four home runs (including a grand slam) and had a career-high 10 RBI against the St. Louis Cardinals.

[15] Batting .326 with 14 home runs and 58 RBIs, Gennett was named to the 2018 Major League Baseball All-Star Game.

[17][18] Gennett's strong seasons with the Reds led to a one-year, $9.78 million deal with the team,[19] but he began the 2019 campaign on the injured list with a severely strained groin.

[22] Gennett's arrival preceded the Giants' decision to let go of long-time second baseman Joe Panik, who was designated for assignment on August 6.

[27] In 2017, Gennett was nominated for the Roberto Clemente Award for his efforts with the Athletes Brand charity campaign titled "K Poverty."

Athletes Brand and Food for the Hungry partnered with Major League Baseball Players to help mitigate poverty in the Dominican Republic.