The winger performed well in United's 1-1 draw with league leaders Arsenal on Sunday but has decided to withdraw from Mark Hughes's party for Wednesday's match due to a niggling hamstring problem.
Giggs has often been criticised for rarely representing his country in friendly matches since making his debut as a teenager in Germany.
The Red Devils have a vital FA Cup semi-final date with Arsenal on Saturday where defeat will effectively signal the end of the champions' season.
Darren Fletcher, perhaps something of a surprise starter at Highbury, is another United man not to be involved in midweek action.
The Scotland international has been withdrawn from Berti Vogts's squad for the home game with Romania due to a groin injury.
Roy Carroll is another to be rested, as he misses Northern Ireland's friendly with Estonia, but Diego Forlan will represent Uruguay against Venezuela so he is highly unlikely to figure at Villa Park.
