With all precincts reporting Wednesday, the city councilman grabbed 54 percent of the votes against his fellow Democrat. Greuel had 46 percent.
Garcetti sent out a tweet thanking voters and saying he's honored to lead the city.
In a statement, outgoing Mayor Antonio Villaraigosa said Garcetti would "guide our city into its bright future. I know I am leaving Los Angeles in good hands."
Garcetti, 42, promised voters to increase jobs and patch up the city's battered streets and sidewalks. He will be the city's first elected Jewish mayor.
Garcetti shares a Latino heritage with the exiting mayor - he has Italian and Mexican roots from his father - but he has a far different resume than Villaraigosa, the product of a broken home from the tough streets east of downtown.
Garcetti is the son of a former district attorney who grew up in the San Fernando Valley's tony Encino enclave, attended Columbia University and enjoys playing jazz piano.
Despite record spending, turnout at polls appeared sluggish after a campaign that centered on the city's ailing economy and the influence of municipal unions. Only 1 of 4 voters in the nation's second-most populous city was projected to cast a ballot, possibly a historic low in a city known to shrug at local politics.
Garcetti takes over on July 1.
A steady stream of negative advertising from the campaigns and outside groups has helped obscure the candidates' promises about free-flowing traffic, new jobs and better schools in coming years.
Garcetti's commercials labeled Greuel "DWP's mayor," a reference to the Department of Water and Power, whose workers financed ads to help install her at City Hall.
Greuel and Garcetti emerged from a March primary in which no candidate secured the majority needed to win outright, leading to Tuesday's runoff. Only about 2 in 10 voters went to the polls in that race.
The mayoral contest has seen record spending - over $30 million overall.
Associated Press writer Andrew Dalton and AP video journalist Raquel Maria Dillon contributed to this report.