England will host world champions Spain in their first home game of the 2025 Nations League.
The rematch of the 2023 World Cup final will take place on Wednesday, 26 February at 20:00 GMT.
Spain are the current holders of the Women's Nations League and sit one place below the Lionesses in the Fifa world rankings.
"It’s very exciting to start 2025 at home in this way," said boss Sarina Wiegman.
"We always want to perform against the best and there’s no doubt that Spain as world champions and Nations League holders are one of the biggest challenges we can face. That's how we will continue to develop and grow in a big year for us.
"The game is made even more special by the fact that it's at Wembley, a place that holds so many memories for the team and our fans. We will need the fans' support, and I hope they're looking forward to what will be another big night under the lights at our home."
Five days earlier, the Lionesses start their Nations League campaign with an away trip to face Portugal, who are ranked 22nd in the world in their first fixture of Group A3 on 21 February.
Scotland travel to Austria in their first game in Group A1 before they host the Netherlands on matchday two.
Wales head to Italy for their opening encounter in Group A4 then have a home fixture with Sweden.
Northern Ireland begin Group B1 with a game in Poland and then host Bosnia and Herzegovina.
Matchday one: 21 February
Austria v Scotland
Portugal v England
Italy v Wales
Poland v Northern Ireland
Matchday two: 25-26 February
Scotland v Netherlands
Wales v Sweden
Northern Ireland v Bosnia and Herzegovina
England v Spain
Matchday three: 4 April
Scotland v Germany
England v Belgium
Wales v Denmark
Romania v Northern Ireland
Matchday four: 8 April
Germany v Scotland
Belgium v England
Sweden v Wales
Northern Ireland v Romania
Matchday five: 30 May
Scotland v Austria
England v Portugal
Denmark v Wales
Northern Ireland v Poland
Matchday six: 3 June
Netherlands v Scotland
Spain v England
Wales v Italy
Bosnia and Herzegovina v Northern Ireland