Entering the 2016 season, MLB.com ranked Moncada as the 7th best prospect in Major League Baseball.
Moncada was called up and made his major league debut on September 2, 2016, against the Oakland Athletics. In his first plate appearance, he walked and subsequently scored a run. He recorded his first major league hit the following day. Moncada finished the 2016 MLB season with a .211 batting average (4-for-19) with one RBI.
On December 6, 2016, the Red Sox traded Moncada, Michael Kopech, Luis Alexander Basabe, and Victor Diaz to the Chicago White Sox for Chris Sale.