The eastbound carriageway was closed until 15:50 BST following the crash near junction 24 Coldra roundabout.
Emergency services were called just before 14:00 BST and two people have been taken to the city's Royal Gwent Hospital.
Highways officials say traffic has now returned to normal levels.
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Two people have been taken to hospital after a crash involving a 4x4 vehicle on the M4 in Newport led to a six-mile tailback.