Anna Martin finished 11 of 15 from the field, including making five of seven 3-pointers.
Kelsey Reynolds scored 15 points, Keisha Hampton added 14, and Brittany Hrynko and Megan Rogowski both added 13 for DePaul (3-1). Hrynko and Rogowski both hit three 3-pointers.
The Blue Demons also held a 48-29 advantage in rebounds. Katherine Harry grabbed nine, and Rogowski and Hampton both had eight.
Martin's 3-pointer in the closing seconds of the first half gave the Blue Demons a 47-24 lead.
The Pilots scored the first seven points of the second half to get within 16, before the Blue Demons took over. DePaul led by as many as 42.
Natalie Day scored 18 points for Portland (2-2).
Martin leads No. 18 DePaul over Portland
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