Exeter brought an end to Dean Glover's bright start as Port Vale manager and extended Vale's dismal home run.
Marcus Stewart drove home from close range after Berti Cozic had headed a 17th-minute corner against a post.
Two minutes later, Liam Sercombe's 20-yard shot looped in after a deflection, before Matt Gill's 65th-minute corner slipped through Joe Anyon's fingers.
Vale managed a consolation goal four minutes from time when Luke Rodgers drove in from close-range.
Port Vale: Anyon, Stockley, Prosser, Collins, McCrory, Dodds (Glover 82), Howland (Rodgers 62), Griffith (Richman 79), Davidson, Paul Edwards, Richards. Subs Not Used: Martin, McCombe.
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