Defoe, 35, was selected to lead the Cherries attack at Stamford Bridge on Wednesday (20 December) but less than two minutes into the contest he was floored by a crunching tackle from 17-year-old defender Ethan Ampadu.
The veteran striker tried to continue but his evening was brought to a close after just 17 minutes with Jordon Ibe coming on to replace him.
Bournemouth's cup journey was brought to an end when Chelsea scored an injury-time winner through Alvaro Morata, despite Dan Gosling scoring a late equaliser for the visitors just moment earlier.
But Howe now has much bigger problems with both Defoe and Harry Harter, another forced off through injury in west London, joining the club's ever-growing injury list.
"It looks like he has potentially got some damage to his ankle ligaments," Howe said following the 2-1 defeat to Chelsea, Reuters report. "It was a nasty tackle. He went over on his ankle, he wasn't right, he had to come off.
"But it meant we lost Jermain and that is going to be a huge blow to us.
"Harry Arter felt his calf and had to come off so we really are stretched. We have a number of players back home who are injured so we hope none of them are too serious."
Joshua King and Charlie Daniels are also on the injury list, forced off during the weekend defeat to Liverpool, missing Wednesday's quarter-final defeat as a result. Tyrone Mings is another absentee as he continues to recover from a back problem.
Howe's side return to Premier League action at home to Everton on Saturday [23 December] where they will try to address an alarming run of form which has seen them fall to 16th, just a point above the relegation zone.