Adam Marriott scored one goal and made another as Cambridge eased past fellow Blue Square Bet Premier promotion chasers Southport.
Marriott gave the hosts an early lead when he finished James Jennings' cross from close range.
He then provided the corner from which Kevin Roberts headed the U's second.
After Southport's Alan Moogan was sent off for a rash challenge on Harrison Dunk, Michael Gash headed in another Jennings cross for Cambridge's third.
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Cambridge United boss Jez George told BBC Radio Cambridgeshire:
"We started the game really positively. I thought we got on the front foot. We looked dangerous going forward.
"I thought a lot of the performance was really good tonight.
"We've also got to be honest and there was a littler spell in the first half where they caused us problems. Our shape without the ball wasn't right.
"But I was pleased with a lot of our attacking play and the intent of our team."