The midfielder joined United in 2018 and was part of their inaugural professional side that won the FA Women's Championship title in the 2018/19 season, securing promotion to the WSL.
The former Liverpool and Juventus player, appointed captain in her second United campaign, made 161 appearances, scoring 32 goals.
"Everyone at Manchester United would like to place on record their thanks to Katie for her excellent service and wish her the best of luck in the next phase of her career," said a club statement.
Zelem led her side to a club-best WSL finish in 2022/23, when United were runners-up and secured Champions League football for the first time.
The 28-year-old, who also has 12 caps for England, made history with United last season when they beat Tottenham 4-0 in the FA Cup final at Wembley in May to secure their first major trophy.
The announcement of Zelem's departure follows Wednesday's confirmation by the club that striker Lucia Garcia will also be leaving.
England's first-choice goalkeeper Mary Earps has been linked with a move to Paris Saint-Germain.
The departures come during a period of uncertainty for the women's team following the takeover of football operations by minority owner Jim Ratcliffe, who said the focus had so far been on the men's team.
