Simmons played youth baseball alongside fellow Curaçao natives Kenley Jansen and Didi Gregorius; he also played basketball and soccer. Due to his slight build, Simmons did not draw much attention from MLB scouts until attending Western Oklahoma State College in Altus, Oklahoma. As a freshman at Western Oklahoma State, Simmons hit .472 with seven home runs and 40 RBIs, leading his team to the 2010 NJCAA Division II College World Series.
Simmons was drafted by the Atlanta Braves in the second round of the 2010 Major League Baseball Draft out of Western Oklahoma State College.
Prior to the 2012 season, Simmons was the Braves' fourth best prospect according to Baseball America. He was ranked 92nd in all of baseball. During spring training he competed with Tyler Pastornicky for the Braves starting shortstop job. On May 30, 2012, the Braves called Simmons up, and he made his Major League debut on June 2 against the Washington Nationals. He got his first Major League hit, a double, on June 3. Simmons was named National League Rookie of the Month for June 2012 after hitting .333 with six doubles, three home runs and 14 RBIs in June 25 games. He led all NL rookies in batting average and on-base percentage. Simmons also won praise for his outstanding defense, and is considered as arguably the best defensive shortstop in the game. On July 8, 2012, during a game against the Philadelphia Phillies, Simmons suffered a non-displaced fracture of the fifth metacarpal on his right hand while sliding head-first into second base. On July 9, he was placed on the 15-day disabled list.
On June 4, 2013, Simmons hit his first walk-off hit. He finished the 2013 season with the highest Defensive Runs Saved ever recorded in a year and received the Gold Glove, the Fielding Bible, and the Rawlings Platinum Glove Award for his defensive work that season.
On February 20, 2014, the Atlanta Braves signed Simmons to a seven-year deal worth $58 million. At the end of the year, Simmons and then-teammate Jason Heyward won the Gold Glove and Fielding Bible for their respective positions.
On November 12, 2015, Simmons, along with catcher Jose Briceno, was traded to the Los Angeles Angels of Anaheim for Erick Aybar, Sean Newcomb and Chris Ellis. In a May 9, 2016, game against the Tampa Bay Rays, Simmons tore the ulnar collateral ligament of his left thumb and was placed on the disabled list. He was reactivated on June 16. He received the Fielding Bible Award for the fourth straight year.
Simmons played for the Netherlands national team at the 2013, and was selected for the team at the 2017 World Baseball Classic.