The fire began in the kitchen on the ground floor of the Regent Plaza hotel, before spreading through the building, local media report.
More than 70 people were injured as the fire trapped guests with few escape options, forcing some to fashion makeshift ropes from bedroom sheets.
Several reports said that foreign nationals were among the injured.
Television footage showed knotted lines of sheets hanging from the building’s windows.
“We tied the bed sheets together to make a rope, and used that to climb down from the fourth floor,” injured man Khalid Mehmood told the AP news agency from his hospital bed.
“We also had to jump mid-way, as the bed sheets weren’t long enough.”
The Associated Press of Pakistan quoted Karachi mayor, Waseem Akhtar, as saying there had been no emergency exit in the building.
Firefighters rescued other guests from the side of the building with ladders.
Another hotel guest, Inna Iqbal, said she had to avoid breathing in smoke before escaping by ladder across the rooftops.
“We were trying to just minimize the smoke damage,” she told reporters.
“We had to break the window at one stage, we felt it was filling up the room too much.”
Dr Seemi Jamali, from the Jinnah Postgraduate Medical Centre, told Reuters news agency that 75 people had been brought to hospital, but most were in stable condition
“All patients are safe and secure. And we have only five patients now left in the emergency,” she said. “The rest of the people who died on the spot, perhaps, were 11.”
Three doctors were among the victims, she added.