A variety of tenants occupy the space, from large law firms to public and not-for-profit agencies like the Lower Manhattan Development Corporation and the World Trade Center Memorial Foundation as well as new businesses.

The lobby and elevators have an extensive security system, and the building has a connection to the New York City Subway's Fulton Street/Fulton Center station (2, ​3​, 4, ​5​, A, ​C, ​E​, J​, N, ​R, ​W, and Z trains) in the basement.

[3] Following the September 11 attacks, and the subsequent collapse of the World Trade Center nearby, One Liberty Plaza sustained significant facade damage.

[6] Morgan Stanley placed a $784 million loan on the tower in August 2017[7] and placed a partial ownership stake on sale for $1.6 billion two months later.

[13][14] One Liberty Plaza is a hub of Wall Street activity, housing RBC Capital Markets' trading floors.

[16] It also houses the corporate headquarters of Empire Blue Cross Blue Shield (part of Anthem),[17] Investment Technology Group, and insurance companies Arch Insurance Group, Sirius America, Mutual of America, Swiss Re, Generali, and Allianz and its subsidiaries Fireman's Fund and Interstate/Chicago.