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After a hard-fought first half that saw both sides struggle to create clear-cut opportunities, in the second half it was the home side who made the all-important breakthrough - as Manuela Giugliano curled home from inside the box.
A penalty, cooly converted by Daniela Sabatino, doubled the advantage - before an Annamaria Serturini cross turned into her own net by Linda Tucceri threatened to make things interesting with 15 minutes remaining.
The Rossonere - fighting for a top two finish in Serie A - would not be destabilised, however, with Valentina Giacinta scoring twice to see out the contest.
The result leaves Roma fourth in Serie A, although they still have work to do to clinch that spot with two games remaining.
"Obviously it's a heavy loss," coach Betty Bavagnoli said afterwards. "But I'm pleased with the first half, where we went toe-to-toe with Milan."
She added: "We paid dearly for the defensive error we made at the start of the second half, and that changed the game. But even at 2-0 we still believed we could bounce back.
"Milan deserve credit, as they made the most of our difficult moments and, especially in attack, had players with a bit more of a cutting edge."
The championship now takes a break for over a week due to international call-ups. Roma's next game is against Pink Bari at Stadio Tre Fontane on April 13.
See the best photos from the match in the gallery below.
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