The knee problem will definitely keep the 25-year-old out of Saturday's clash with Chelsea at Goodison Park.
Rumours are already starting to circulate that Calvert-Lewin could be facing three months on the sidelines and so-called scans have revealed a tear to his lateral collateral ligament, although Everton are downplaying any fears.
Calvert-Lewin, who missed four months of last season with a persistent muscle injury, is being assessed by Everton's medical staff and undergoing treatment.
"We'll miss him for Chelsea. He was looking in great physical condition and was training really well. It was a freak injury in training, which does happen.
"It's a shame but we have to find the solutions to keep ourselves strong without Dominic before he returns."
Calvert-Lewin missed Everton's friendly at Blackpool, then scored the opening goal in the 3-0 win over Dynamo Kyiv last Friday.
Everton have serious issues in the striker department ahead of the clash with Chelsea, especially as Salomon Rondon is suspended.
They are likely to use their attacking midfielders to plug holes, with Dele Alli possibly being used in a 'false nine'. Youth academy prospect Lewis Dobbin could also be called upon.