President Donald Trump, who owns the building and resides in the penthouse when he is in NY, was in Washington DC at the time of the blaze.
There were no immediate reports of injuries.
As firefighters battled the blaze, a plume of smoke spewed from the roof of the 68-story structure, which had been Trump's primary residence before his election victory and inauguration almost a year ago.
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Trump Tower retains a large security presence and is often protected during large public events in Manhattan.
The third injured person was a civilian who received treatment at the scene, according to the FDNY's Twitter account.
Debris fell on a firefighter during the incident and an engineer using a fire extinguisher to try and stop the fire inhaled smoke, said FDNY Manhattan Borough Commander Roger W. Sakowich.
Trump Tower was also the setting for Trump's reality TV show, "The Apprentice", and the headquarters of his presidential campaign.
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The fire seemed larger than reported because of the amount of smoke billowing from the roof of the skyscraper.
The president was in Washington DC at the time. The fire department was called shortly before 7 a.m.
The president's son Eric tweeted his thanks to firefighters for doing "an incredible job". NY time, reportedly by Secret Service agents. "The men and women of the #FDNY are true heroes and deserve our most honest thanks and praise!"
The building houses luxury apartments as well as business establishments. How fitting. A sign from God", one wrote, while another added, "Hope Trump likes all the fire and fury happening on top of his tower right now.
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