After an opening group-stage defeat to Uruguay, England coach Brian Eastick told his troops to lift their game against the powerful West Africans.
But his pre-game preparations were hit when four first-choice players were laid low by a stomach virus while opposite number Sellas Tettah kept the same side who beat Uzbekistan in their opener.
Despite their problems England started brightly and could have taken the lead when Jonathan Obika saw his header crash against the crossbar in the ninth minute.
But that was to be as good as it got for England as Ghana established control of what became a one-sided encounter.
Ghana have now secured progress to the last 16 while Eastick's side – who have gone eight matches at the U20 World Cup without scoring – must beat Uzbekistan by a considerable margin on Friday to stand a chance of progression.
Mohammed Rabiu was a constant threat but it was Dominic Adiyiah who broke the deadlock, an expert first touch unlocking England's defence while a classy finish left goalkeeper Elliott Parish flat-footed.
Skipper Andre Ayew doubled the advantage with a wonder finish, drilling the rising ball into the top corner as three England defenders just stood and watched.
England - a team packed with talent from Premier League academies - never seemed up for the challenge of mounting a comeback, as U21 boss Stuart Pearce watched with concern from the stands.
Their fate was sealed when Ransford Osei's goalbound shot took a wicked deflection past Parish while Adiyah added his second with just two minutes to go.