Clinton Morrison and Alex Gilbey were both denied by Colchester goalkeeper Bartosz Bialkowski early on.
But County went ahead just before the half-hour through Jack Grealish, who had time to fire past Sam Walker following Jamal Campbell-Ryce's low cross.
Jabo Ibehre stabbed a good chance wide for Colchester, but County doubled their lead just before the break when Morgan Fox slotted home from close range from Callum Ball's low cross.
Magnus Okuonghae blasted over for Colchester from close range early in the second half, as the home side tried hard to carve out openings for a route back into the contest.
But after the impressive Grealish saw his fine left-footed shot come back off the post, Callum McGregor scored a third for the Magpies with three minutes left with a sweet strike.
Gary Liddle wrapped up victory for County in the final minute with a nonchalant finish following Grealish's pass.