Bernardello, the gritty Argentine who looked to have settled the team's midfield in his four appearances, will be out four to six weeks with a sprained left ankle after taking a knock in a 0-0 tie in Philadelphia last Saturday.
And Lopez, a defender who had seen action in only one CONCACAF Champions League match, will be out at least six months with a right knee injury suffered during practice on Tuesday.
Add to that the absence of midfielder Andres Romero on a brief paternity leave and the Impact will be shorthanded when they go on the road to face the New England Revolution on Sunday night.
"That's part of the sport and we can't spend all day crying about it," Montreal coach Marco Schallibaum said this week. "Now we have to find a solution."
The Impact (12-7-6) go into the weekend in a three-way tie for first place in the MLS Eastern Conference, with two games in hand each on the New York Red Bulls and Sporting Kansas City.
The Revolution (10-9-7) are in fifth spot.
The loss of Bernardello, the team's second designated player after striker Marco Di Vaio, and Spanish central defender Lopez leaves them with essentially the same team as before the signings.
That outfit had been good enough to put them safely in playoff position, but it reduces Montreal's depth heading into a busy month of league and CONCACAF action.
The toughest loss is Bernardello, who had become a key piece alongside veteran Patrice Bernier at the back of the midfield, both in shoring up the defence and moving the ball forward.
"It's a pain for him too because he was doing well," said Montreal left back Hassoun Camara. "He brought a lot of stability to the midfield. But we have to work with the players we have."
Schallibaum tried out different players and formations in practice this week to make up for Bernardello and Romero, who had become a regular starter on the left side in recent games. Romero returned to Argentina, where his wife was due to give birth, and is expected back on Monday.
Collen Warner may move into Bernardello's spot, while Davy Arnaud should be back in the starting 11, possibly in the middle. Sanna Nyassi is another strong candidate, particularly in Romero's spot on the left side.
"I feel bad for those two guys, to come into a new group and both get hurt in the same week," said Arnaud. "It's unfortunate, but things happen during a season and we have to continue moving forward."
Arnaud got bumped from the lineup when Bernardello moved in and has been used off the bench in recent games.
It was the first time since the team captain was acquired last year for the team's MLS expansion season that the 33-year-old has been used through a stretch of games as a substitute.
"It's not easy." said Arnaud. "I want to be on the field every minute of every game.
"That's my mentality and that's who I am. That won't change. But then again, we won a game 5-0 against Houston and you can't expect too many changes after a result like that.
"But I continue to do the things I do. I'll be back on the field soon enough. You respect the coach's decisions all the time, but it doesn't mean I don't want to be out there."
While Lopez will not return until sometime in 2014, Bernardello hopes to be back before the end of the regular season.
"At the time, I didn't think it was that bad," Bernardello said of the injury. "I tried to keep playing, but I couldn't.
"I was feeling good after nearly a month with the team, so it's really too bad. But there's no choice but to recover and get back in. They're saying four to six weeks, but me, I think I can come back earlier. I hope so, anyway."
Fate has not fixed itself totally against the Impact, however.
For one, they will play on a grass field, just like at home. The Revolution normally play on an artificial surface, but grass has been laid down at Gillette Stadium, mainly for a Brazil-Portugal friendly on Sept. 10. That will be a relief for defender Alessandro Nesta, who has played through a nagging groin problem.
They will also have Schallibaum back after serving a two-game suspension, his fourth ban of the year, for losing his temper on the sideline against Houston. Assistant coach Mauro Biello went 1-0-1 as interim head coach.
"He brings a lot of passion to the game at the sideline and as a player you feed off that," Arnaud said of Schallibaum. "He's into the game.
"The players don't have any problem with the things that have happened, to be honest, because a lot of times he's reacting to protect the players. You appreciate that."
The Impact are 3-6-3 on the road this season, but they won in New England in 2012.
Both teams are on three-game unbeaten runs, with New England coming off a 1-1 draw last week in Toronto.
The Impact will have an eye on Kelyn Rowe, who has three goals in three games, and Diego Fagundez, who has two goals and an assist in the Revolution's last three matches.
New England will be without newly signed left back O'Brian Woodbine, who is on national team duty with Jamaica.