Sunderland striker was overlooked despite an excellent season.
Defoe, who has previously netted a hat-trick for England and also scored at the 2010 World Cup, missed out in favour of Manchester United talent Marcus Rashford, who has broken into the first team this season.
Defoe's goals were the key factor in Sunderland retaining their Premer League status, scoring 15 in total. Wayne Rooney on the other hand has netted just seven.
While his omission did not come as a complete surprise considering he has not been in recent squads, the injury suffered to Arsenal striker Danny Welbeck last week offered a glimmer of hope that Defoe could be brought back in contention.
England boss Roy Hodgson has opted for youth instead and while commendable, Defoe would not have let England down and would have been worthy of selection.
His absence can be Sunderland's gain, with Defoe now likely to be fully rested up ahead of next season after his heroics this campaign, but fans of the Black Cats have provided mixed responses at the striker being overlooked.
Here is a look at how fans reacted on Twitter...
Absolute disgrace that Defoe has not been named for England team #safc— Jane Cuthbertson (@cubbysafc) May 16, 2016
Whenever Rashford misses a sitter to win a must win game in the Euro's, lets just remember that Defoe wasnt pick for him #SAFC— Chris (@TheIrishMackem) May 16, 2016
Just means Defoe can have a good rest this summer and come back raring to go in pre-season #safc— AlanSAFC (@AlanJWatson) May 16, 2016
and this has nowt to do with Defoe not being in the squad, I am glad he isn't, imagine him getting injured man #SAFC— Alan Smith (@al_smith11) May 16, 2016