Cuomo had far greater financial resources going into the matchup, and polls suggested he held a commanding lead before Thursday's primary.
Nixon, an activist and former "Sex and the City" star, had hoped to become the latest liberal challenger to unseat a powerful insider.
Cuomo's campaign dismissed her as inexperienced and touted the governor's work to push back against President Donald Trump.
His victory comes despite several missteps, including a widely condemned mailer that questioned Nixon's support for Jewish people. Nixon has two Jewish children and called the attack "sleazy."
Cuomo will face Republican Marc Molinaro and independent Stephanie Miner in November's general election.