Ciaran Clark and Rob Elliot remain doubtful for the clash against the Toffees but Longstaff, who was taken off at half-time in United's 2-0 defeat at West Ham, has suffered a knee ligament injury and will almost certainly play no further part this season.
The 21-year-old Academy graduate has been in fine form since breaking into the first team in December, earning a nomination for the Premier League's Player of the Month for February after 11 consecutive starts for the Magpies.
Despite the disappointing blow, Benítez maintains a strong roster of central midfielders in his Premier League side, with Isaac Hayden, Mohamed Diamé, Ki Sung-yueng and Jonjo Shelvey targeting a first team spot.
"When you have an injury in your team, it's always bad news," said Benítez. "For a young player it's even worse. Talking with him, he's fine mentally - he's strong enough. He knows he needs to start working to get fit as soon as possible. His reaction has been really positive, but we're disappointed with the injury.
"He was training well with us but nobody was expecting that he could settle down so quickly and play so well, ending up being a key player for us. It's a pity for him and for the team but, if you look at (Florian) Lejeune, you can come back quickly from injuries.
"It is not as serious. He is unlikely to be back this season, but mentally he is fine and he will be back in two to three months. He was becoming a key player for us but he will be fine in the future.
"We have to make a decision - we had five midfielders the other day, and now we have four. It is bad luck for Sean but it could be good luck for another one. Hopefully, the next one who will play in his position can do as well as him."
Everton lie in tenth place of the top flight on 37 points, six points ahead of United, who are seeking their fifth straight victory at St. James' Park.
However, Benítez expects Marco Silva's men to pose a difficult task for the Magpies, with the Merseyside club recently defeating Cardiff 3-0 as well as shutting out title challengers Liverpool in a goalless draw last weekend.
Benítez added: "At the beginning we played top sides, but now we have gained confidence we didn't have before. The team was playing well, the fans were supporting the players and the atmosphere has been positive (at St. James' Park).
"The passion is helping us. It is easier when you are doing well, especially against top sides. The players play with the intensity and the passion that everyone is asking for.
"For us, every game is like a final. They (Everton) have the same feeling. It was a difficult game when we played at Goodison Park as they were passing the ball really well.
"We did well and it was a good game for us in terms of team spirit and the way we were defending and playing on the counter-attack. They have some good players and it will be a tough game if they approach the game in the right mentality.
"They are quite confident after the derby - they were working so hard and they did well against one of the best teams in the league. That means they will come here with a lot of confidence and it will be a difficult game."
