The protests broke out on Friday with demonstrators throwing rocks and setting fire to buildings. Police fired back with tear gas and live ammunition.
Friday is a government-declared special day of love for the Prophet Muhammad. The normally busy streets of Karachi's commercial and industrial area are nearly deserted in observance of the holiday. However, the port city was the scene of most of the violence with 12 deaths and 82 injuries, according to hospital officials. Also, five people were killed and 60 wounded in the northwestern city of Peshawar, police said.
Muslims also marched in at least a half-dozen other countries, with some burning American flags and effigies of U.S. President Barack Obama.
Pakistan has experienced nearly a week of deadly protests over the film, "Innocence of Muslims." The movie, which was produced in the U.S., has sparked anti-American violence around the Islamic world since it attracted attention on the Internet in the past 10 days.
At least 47 deaths have been attributed to violence over the film, including the death of the U.S. ambassador to Libya. The film denigrates the Prophet Muhammad, portraying him as a womanizer and a child molester.
The Associated Press contributed to this report.