Defoe, who has scored all three of Toronto's goals this season, has been sidelined by a slight hamstring strain while Caldwell must serve a suspension. And the injury list could be longer with midfielder Jonathan Osorio facing a second week out with his own hamstring issue.
Manager Ryan Nelsen says Defoe, who had a scan Tuesday after leaving Saturday's game in Salt Lake City early, will be out "for the short-term."
"Not a major thing but definitely unavailable this weekend," he said.
The 31-year-old England striker was substituted in the 61st minute Saturday favouring the back of his left thigh as he went to the dressing room.
Caldwell was suspended one game and fined an undisclosed amount Wednesday for what MLS called "serious foul play that endangers the safety of an opponent."
The hard-nosed Scottish centre back — TFC's captain — was yellow-carded for a studs-up tackle on midfielder Ned Grabavoy in the 3-0 loss to Real Salt Lake.
Toronto had hoped to avoid a ban, arguing that the referee had seen the incident and decided on the appropriate punishment. But the league's disciplinary committee disagreed.
While Caldwell insisted he was just trying to win the ball, it was an ugly challenge that could have merited a straight red card, which carries with it a minimum one-game suspension.
Caldwell is the second Toronto FC player to receive supplemental discipline. Brazilian midfielder Jackson missed the Salt Lake game after getting a one-game ban for an elbow thrown away from the ball in a 1-0 win over D.C. United.
The latest suspension is especially worrying because Doneil Henry, Caldwell's partner in central defence, has not trained this week because of a jarred knee suffered in Salt Lake City.
"There could be a few guys unavailable," said Nelsen, who has repeatedly noted that the teams that succeed in MLS are the ones with the depth to cover such absences.
The Toronto manager, who brought in as many as eight new starters in the off-season, is on the lookout for such reserve talent.
"They normally play under the radar, they don't get any publicity or anything like that. They're the most valuable players on MLS teams and Toronto hasn't had those type of guys. We're trying to build them, we're trying to get them, we're trying to bring them (in), we're trying to develop them ourselves.
"For me, (the time) we'll get very, very, very good is when we can have a number of those guys who throw out seven of 10 (performances) every week."
Goalkeeper Julio Cesar, who also took a knock to the knee on the weekend, was back in training Wednesday. And Toronto has Jackson back from suspension.
Nelsen declined to say who will partner Brazilian striker Gilberto on Saturday against the unbeaten Crew (3-0-0).
Nelsen played Canadian international Dwayne De Rosario up front with Defoe in the opening game of the season in Seattle when Gilberto was not ready.
He pointed to De Rosario, Jackson, Andrew Wiedeman and newly signed Issey Nakajima-Farran as possible options.
There was no "woe is me" from Nelsen.
"Jermain's come in and done really well obviously. But he got a slight strain and we move on. That's life."
On the backline, Nelsen has Gale Agbossoumonde and rookie Nick Hagglund at his disposal. American Justin Morrow could also move in from the left flank.
Reserve fullback Ashtone Morgan is also dealing with a sore hip.
Nelsen has spoken at length the last two days on the league's supplemental discipline, arguing that it can undermine referees when the league rules on incidents that the on-field officials have already ruled on.
"I don't know why the league needs to get involved, to tell you the truth," he said Wednesday.
Still he seemed to want to have his cake and eat it too when, awaiting word last week on the Jackson suspension, he argued that Real Salt Lake forward Alvaro Saborio deserved a ban for his foul on A.J. DeLaGarza of the Los Angeles Galaxy the previous week.
"That could have broken his leg,'' Nelsen said at the time of the Saborio challenge. "So if Jackson gets suspended, then you'd like to hope that a guy who's nearly broken a guy's leg is probably going to get suspended as well.
"But I don't know, you never know. I don't make those rules.''
Nelsen was no doubt aware that RSL was already facing a glut of injuries at forward.
His argument is that such supplemental discipline sets a precedent, effectively prompting all clubs to seek justice.
"So do we slow down all elbows that were hit on Jackson before he did one or the elbow on Steven before that tackle?" he asked. "It's a slippery slope isn't it when you start overturning referees and taking away the human element of it, then every single team will have cases every single week."
Unlike the NHL, MLS players are still paid while suspended.
Also Wednesday, the league's disciplinary committee fined Colorado Rapids defender Drew Moor an undisclosed amount for swinging his arm at the back of Sporting Kansas City forward Claudio Bieler's head.
According to the league, the disciplinary committee's mission statement is "to preserve the integrity and reputation of the game and Major League Soccer, and to assist in ensuring player safety."
The committee can take further action when the referee has seen or ruled on an incident on the field, if there is unanimous opinion that the play deserved a red card or was of "an egregious or reckless nature, such that the committee must act to protect player safety or the integrity of the game."