Oxford sit 51 places below West Ham on the English football pyramid, but that didn't stop a second-half demolition that saw Oxford score four in the final 35 minutes.
West Ham made nine changes after the 2-0 win over Manchester United at the London Stadium on the weekend.
However their line-up still included senior players such as Pablo Zabaleta, Jack Wilshere, Robert Snodgrass and Issa Diop, with Felipe Anderson and Sebastien Haller coming off the bench in the second half.
Oxford struck first through Elliott Moore before Matty Taylor, Tariqe Fosu and Shandon Baptiste completed the rout.
West Ham manager Manuel Pellegrini took full responsibility for the defeat.
“The whole team didn’t play well. Not only did we concede four goals, but we didn’t create too many chances,” Pellegrini said.
“We missed too many passes from the beginning and the responsibility is first on me because I picked the players and second of course on the team that didn’t compete.
“We talked enough with all of them to understand that the competition was different, the team was different and to play now against Oxford, who were in a good moment after winning 6-0 [at Lincoln] in their last game.
“The players must understand, but I repeat we couldn’t do it because in front was a team that played very well. I don’t want to take anything away from Oxford because they played very well.”
