Speaking during a visit to a new US marine base in southern Helmand province, Gen McChrystal said that US and Nato troops must make a "cultural shift" from conventional warfare to protecting Afghan civilians.
"Traditionally American forces are designed for conventional, high-intensity combat. In my mind what we've really got to do is make a cultural shift," he said
"When you do anything that harms the people you just have a huge chance of alienating the population. And so even with the best of intentions, if our operation causes them to lose property or loved ones, there is almost no way somebody cannot be impacted in how they view the government and us, the coalition forces."
Gen McChrystal, who took command of the 56,000 US troops and 32,000 Nato-led forces in Afghanistan last week, is due within days to release new guidelines on minimising civilian deaths.
They are expected to advise troops to break off from firefights with the Taliban rather than call in air strikes that might kill civilians.
The deputy commander of Nato-led forces in Afghanistan, Jim Dutton, said a "fundamental mindset change" had been taking place for some time and was now being reinforced under Gen McChrystal.
"If you are in a situation where you are under fire from the enemy... if there is any chance of creating civilian casualties or if you don't know whether you will create civilian casualties, if you can withdraw from that situation without firing, then you must do so," he told the BBC.
The changes come amid increased tension between Kabul and Washington over the number of civilian casualties.
The deadliest recent US air raid was in western Farah province in May.
The US has admitted that at least 26 people were killed, but the Afghan government and human rights groups say the toll was more than 100.
A US military report blamed the civilian deaths on a failure by US forces to follow procedures in air strikes.
The UN says US, Nato and Afghan forces killed 829 civilians while fighting Taliban insurgents last year.
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