Twelve of the deaths -- including at least one policeman -- were as a result of gunfire after clashes between authorities and demonstrators erupted in the southern port city of Karachi.
At least three deaths were reported in Peshawar, where protesters burned two cinemas and the Chamber of Commerce. One of the dead in Peshawar was a driver for an ARY television crew that was sent to cover the unrest. His car was sprayed with bullets as police clashed with the enraged crowd.
Doctors in Peshawar said some 60 people were wounded.
Protesters in Lahore, Karachi, and Islamabad all clashed with police as they tried to reach U.S. and French diplomatic buildings.
In the town of Muzaffarabad, young schoolgirls joined a rally and chanted for the makers of the film and the publishers of French political cartoon to be beheaded. "Punishment for the blasphemer is beheading!" they chanted.
Also on September 21, the UN's human rights agency condemned the film and images at the heart of the controversy but also decried the violent responses to them around the Muslim world.
UN High Commissioner for Human Rights Navi Pillay's spokesman, Rupert Colville, told reporters in Geneva that "both the film and the cartoons are malicious and deliberately provocative." But he added, "There's no possible justification for violent and destructive reactions."
Colville added, "In our view, the best way to deal with these blatantly deliberate, stupid provocations is to ignore them and deprive them of publicity."
On Pakistan's Streets
In Rawalpindi, a military garrison town near Islamabad, protesters threw stones at cars and police and burned down a toll plaza.
In Islamabad, police fired tear gas and live rounds into the air as protesters tried to enter the city. Pakistani authorities had already blocked the road using shipping containers.
In Islamabad, protesters chanted anti-American slogans as they demonstrated near a diplomatic compound where the U.S., French, and British embassies are located. The diplomatic compound was also sealed off in anticipation of the September 21 protests.
PHOTO GALLERY: Pakistanis protest in Islamabad.
Authorities in Pakistan had blocked mobile-phone service in major cities. A Pakistani Interior Ministry official speaking under condition of anonymity told media that cell-phone service had been blocked in at least 15 cities, including Islamabad, Lahore, and Karachi.
Officials privately cited fears militants could use mobile phones to detonate explosives during protests. Phone service was expected to be restored after 6 p.m. local time.
Already faced with a rash of tense protests over the "The Innocence of Muslims" film, Pakistan officially declared September 21 a holiday for a "Day of Love for the Prophet Muhammad" and urged people to protest peacefully.
Pakistani Prime Minister Raja Pervez Ashraf called the low-budget film, which sparked the wave of violence throughout the Muslim world, the "worst kind of bigotry."
"Let me make it absolutely clear: This is not about freedom of expression; this is more about hatred, and it also demonstrates blatant double-standards," Ashraf said.
"If denying the Holocaust is a crime, then is it not fair and legitimate for Muslims to demand that denigrating and demeaning Islam's holiest personality is no less a crime? In this context, we appreciate those in the international community who have joined Muslims in strongly condemning this outrage."
In at least half a dozen other countries, demonstrators also burned U.S. flags and effigies of U.S. President Barack Obama.
The protests in other countries were relatively peaceful compared to the deadly violence in Pakistan.
In Malaysia, thousands of people held a peaceful demonstration in the capital, Kuala Lumpur, to protest the film.
Malaysian Prime Minister Najib Razak called the film "deeply offensive." But he added, "Now, more than ever, each of us has a responsibility to work together for greater respect, tolerance, and understanding so we may live in harmony."
France, where cartoons of Muhammad were published in a magazine, had ordered all its embassies and diplomatic posts in Muslim countries closed on September 21.
France's Interior Ministry also banned all protests in France. Interior Minister Manuel Valls said there would be "strictly no exceptions," and that any crowd of protesters defying the ban would be broken up.