A US-led international coalition has been carrying out air strikes against the IS group in Iraq and Syria since 2014, and nongovernmental organisations say the attacks are claiming ever more civilian lives.
Interviewed on CBS's "Face the Nation" program, Mattis said that "civilian casualties are a fact of life in this sort of situation."
But he quickly added that "we do everything humanly possible, consistent with military necessity, taking many chances to avoid civilian casualties -- at all costs."
But the Pentagon contests both the NGOs' death counts and the charge that a new sense of urgency under Trump is to blame.
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"We have not changed the rules of engagement," Mattis said. "There is no relaxation of our intention to protect the innocent."
The coalition has officially acknowledged responsibility for more than 450 civilian deaths since its bombing campaign began in 2014, including 105 in the Iraqi city of Mosul on March 17.
Although the Pentagon on Thursday acknowledged that an American bombing attack in Mosul on March 17 claimed at least 105 civilian lives, it blamed munitions stored by the jihadists in the houses targeted.
That, Mattis said Sunday, showed "once again the callous disregard that is characterised by every operation they have run.