In 2018, it was reported that Nixon was preparing a progressive challenge to the incumbent governor of New York, Andrew Cuomo. On March 19, 2018, she announced via Twitter that she was running for governor.
Nixon was expected to secure the nomination of the Working Families Party of New York during its annual convention in April 2018, thus guaranteeing her a spot on the general election ballot. On April 15, Nixon won 91.5 percent of the vote at the Party's statewide committee meeting after Cuomo withdrew himself from consideration at the last minute. Nixon stated that in the event that she did not also secure the Democratic nomination, she would "confer with the Working Families Party and we will make the decision we think is best".
The endorsement caused a schism in the party, as labor unions, including the Service Employees International Union, and Communications Workers of America, indicated they would not support the party in the election. The withdrawal, it was believed, would significantly hurt the party's finances which, in 2018, were at a level of $1.7 million and supported a statewide staff of about 15 people. The battle received considerable attention since there were concerns that Nixon might drain enough votes from Cuomo in the general election to allow a Republican to be elected (although Cuomo was comfortably leading the polls at the time). Cuomo had vigorously campaigned to get the nomination before withdrawing when it was clear he would not get it.
On May 23, 2018, Nixon and other potential Democratic challengers to Cuomo were eliminated from the Democratic party endorsement at the state Democratic Convention after failing to meet the 25% state delegate threshold needed to appear on the ballot. Nixon filed a petition with 65,000 signatures, more than four times the 15,000 required, to force a primary election. The primary was held on September 13. With 93% of precincts reporting, Cuomo received 65% of votes and Nixon got 35%. On October 5, 2018, the Working Families Party removed Nixon's name from their ticket after agreeing to endorse Cuomo and Hochul, thus ensuring that Nixon would not appear on the general election ballot.