McKiernan said international forces did make mistakes - "and for that I apologise" - but that US and Nato forces were working hard to minimise civilian casualties during operations.
Karzai had asked McKiernan to explain reports that civilians were killed in a number of recent incidents.
McKiernan was repeatedly questioned on the topic at a news conference in Kabul on Sunday, and he said international forces investigated all allegations and paid compensation for any wrongful deaths.
"Apologies are not sufficient, so we do try to compensate families and communities where we've made mistakes. But that's not sufficient either.
"In fact, there is nothing I could do or say that would replace the loss of a loved one," the general said.
"There's not enough money in the world to replace the loss of a family member."
Helmand deaths
Karzai's office said three civilians were killed by international forces in Helmand province on Friday.
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"There are sanctuary areas that have existed for many years across the border. They feed terrorism and insecurity on both sides of the border"
General David McKiernan,
Nato commander
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The Nato-led force said three people were killed when its forces fired on a vehicle as a man who was "posing a threat" stepped out of it. Two people inside the vehicle were also killed, it said.
Karzai's office also said three civilians were killed in Logar province on Saturday, but the Nato-led force said it had been attacked with machine guns and grenades, and that the people killed were not civilians.
McKiernan also said Pakistan must do more to "erase" Taliban bases inside its territory.
"There are sanctuary areas that have existed for many years across the border. They feed terrorism and insecurity on both sides of the border," he said.
"I think it is safe to say there is an expectation that the government of Pakistan must erase these safe havens so that they are not a threat to their own country and the region. They will have the full support of the international community to do
that."
The US accuses Pakistan of not doing enough to crack down on fighters who cross the border to attack US and Nato troops in Afghanistan.
Taliban attacks
Taliban attacks in Afghanistan have increased to the highest levels seen since the group was driven from Kabul in 2001.
Abdul Rahim Wardak, the Afghan defence minister, talking alongside McKiernan in Sunday's news conference, said: "Challenges, generally, have increased in past years,"
"The level of enemy attacks have gone up, there are foreign combatants [in their ranks], the way they operate has become complex, they have access to better training and equipment."
The US administration has pledged 21,000 more troops to join the 39,000 US soldiers already deployed in Afghanistan.
McKiernan said he would send most of the new troops to southern provinces near Pakistan where instability had risen the most.