The incident happened during a party at the Blythswood Square hotel shortly before 5am.
A foot-long spoke from nearby metal railings was reported to be lying on West George Street, where the 19-year-old landed.
Inspector Kenny Darroch said: “There was a small group who appeared to have been at a party in the penthouse and the man has fallen.
“He is now at Glasgow Royal Infirmary. He’s alive but he has horrendous injuries.”
A spokeswoman for the Scottish Ambulance Service said: “We got a call at 4.55am about a 19-year-old male lying in the street.
“There is suggestion that he’s fallen off the roof. We’ve take him to Glasgow Royal Infirmary.”
The road was cordoned off and police officers remained at the scene late into the morning.
Inspector Darroch said: “We’re preserving it while we take photographs, do a bit of analysis and take statements.”
A single suited officer from the CID arrived at 8:30am, carrying two brief cases.
A police officer at the scene who asked not to be named said: “There is no investigation – we’re not looking for anyone – but there’s obviously protocol to follow.”
The hotel’s Managing Director Hans Rissmann declined to comment on the incident.
The £1500-per-night penthouse is described as “magnificent” on the Blythswood Square website.
It has a rooftop terrace, private bar and dining room and boasts views over the city which “will quite literally take your breath away”, the website said, with guests receiving a bottle of Dom Perignon 2003, Epernay Champagne in their room on arrival.
A spokeswoman for Police Scotland said: “Around 5am a report was received of a man having fallen from the roof of a building in the centre of Glasgow.
“We’re still trying to piece together the circumstances.”
She added: “Road closures will remain in place for quite some time.”