Large crowds have gathered in other cities, but the numbers appear well short of the million protesters predicted by the organisers.
As the protests continued, the leader of one of the main Islamist parties, Qazi Hussein Ahmed, condemned a decision by the authorities to stop him travelling to join in a protest.
Tight security
The crowds in Karachi carried banners with slogans such as "Osama is our hero" and "There are no terrorists in Afghanistan".
There were also calls by senior Islamic party figures for General Musharraf to be overthrown.
More than 5,000 police were deployed to prevent trouble and there were no reports of any violence.
In the western city of Quetta, about 20,000 protesters marched to a disused cricket ground after Friday prayers, denouncing the US raids.
Police in Lahore are reported to have clashed with protesters.
Rights 'violated'
Qazi Hussein Ahmad of the Jamaat-e-Islami told the BBC that his constitutional rights had been violated after he was prevented at Islamabad airport from boarding a flight to Quetta.
Mr Ahmed said he planned to lodge an appeal against the decision.
He also said the public campaign against the war would continue.
Qazi Hussein Ahmad has been one of the main figures in the protests against the American raids.
Two other leaders are currently under house arrest.
There were clashes between protesters opposing the raids and police earlier this month.
Several people were wounded and four people were killed in and around Quetta.
Meanwhile, Mowlana Sufi Mohammad, the leader of a militant Islamist organisation mainly based in the tribal region of northern Pakistan, has announced plans to lead a large militia into Afghanistan on Saturday.
Mowlana Mohammad called on his supporters to prepare for a holy war against the US-led coalition soon after US and British forces launched air and missile attacks on Afghanistan.