O'Melveny's 20-year lease covers slightly more than 200,000sq ft in the 1.2m sq ft building and will accommodate the firm's 210 lawyers, bolstered by last year's merger with private equity specialist O'Sullivan.
The firm is currently housed in two buildings: 30 Rockefeller Center and the Citigroup Center.
The Boston Properties Inc-owned Times Square Tower was in danger of becoming New York's white elephant after Arthur Andersen last year buckled under the weight of the Enron scandal.
As part of the deal, Boston Properties has agreed to release O'Melveny from its lease at Citibank Center, which is also owned by the developer, two years early.
O'Melveny is the first tenant to take space in the building, but Boston Properties hopes that it will attract more law firms to the tower.
Clifford Chance was one firm initially tempted into taking space in the tower. But the firm finally opted to take space in its client's Deutsche Bank Building.