England will take on Croatia and Spain in their UEFA Nations League Group while World Cup holders Germany face France and Netherlands.
Gareth Southgate's side last played Spain in November 2016, where they battled out an entertaining 2-2 draw with Isco grabbing a late equaliser at Wembley.
Elsewhere, Euro 2016 winners Portugal will face Italy and Poland, while Roberto Martinez's Belgium take on Iceland and Switzerland.
The Nations League is designed to replace most friendlies in Europe while allowing teams to play against those who are equally ranked.
The new competition is set to start Sept. 6, with teams playing those in their groups home and away, before a draw for the top-division finals in December. The finals, which include semifinals and a third-placed game, will be held in June 2019.
The Nations League will also offer a second chance for those who do not qualify for Euro 2020 via the normal route. The best-placed nation in each group not yet qualified for the Euros will form a four-team playoff for that division in March 2020. The four playoff winners will then qualify for the Euros.
The event also features promotion and relegation for future editions. At the end of the group stages, those who finish bottom of the groups will be relegated to the league below and four teams will be promoted to the league above.
In the second division, Wales face a replay of the 2018 World Cup playoff qualifier against Republic of Ireland with both nations paired alongside Denmark. Northern Ireland will play Bosnia and Herzegovina along with Austria.
New Wales manager Ryan Giggs has already set his sights on promotion to the top flight.
"There is so much riding on each game, so it won't be hard to stimulate the players," Giggs said in an interview on the Football Association of Wales' Facebook page. "You want to get into League A -- to be playing against England, Spain, France -- and of course you obviously don't want to get relegated, but there is that carrot as well that you can qualify for the Euros."
France manager Didier Deschamps was in playful mood after being dropped into a difficult-looking Group A1 with reigning world champions Germany and the Netherlands.
"Everything's fine, we have an easy draw," the 1998 World Cup and Euro 2000 winner joked to L'Equipe. "Given the way the league is set up, of course there are the best European teams. It's a high quality group, that's the principle of this league.
"Playing prestigious matches with something at stake, it gives the group winner the chance to reach the final tournament. It's a good thing for everyone, for the big and the small nations.
"It's difficult today to find opponents for friendlies. It's a new, interesting competition. They quality of our opponents will give us some great games."
Elsewhere, Germany manager Joachim Low was feeling equally as satisfied.
"It's super interesting," he told Bild. "Netherlands and France, they are our neighbours with a lot of football culture and a long football history. Those are interesting matches for our fans and everyone else."
Belgium's Roberto Martinez believes this competition is a step forward for international football following his team's draw with Iceland and Switzerland.
"I'm very excited for the tournament," Martinez told W Radio. "The most important thing is the format of this competition, which is a step forward.
"The players will want to win to get the trophy, and I think that it has value. The draw couldn't be a surprise because all the teams had been very high in the rankings for many years."
NATIONS LEAGUE GROUP A
Group 1: Netherlands, France, Germany
Group 2: Iceland, Switzerland, Belgium
Group 3: Poland, Italy, Portugal
Group 4: Spain, England, Croatia
NATIONS LEAGUE GROUP B
Group 1: Czech Republic, Ukraine, Slovakia
Group 2: Turkey, Sweden, Russia
Group 3: Northern Ireland, Bosnia and Herzegovina, Austria
Group 4: Denmark, Republic of Ireland, Wales
NATIONS LEAGUE GROUP C
Group 1: Israel, Albania, Scotland
Group 2: Estonia, Finland, Greece, Hungary
Group 3: Cyprus, Bulgaria, Norway, Slovenia
Group 4: Lithuania, Montenegro, Serbia, Romania
NATIONS LEAGUE GROUP D
Group 1: Andorra, Kazakhstan, Latvia, Georgia
Group 2: San Marino, Moldova, Luxembourg, Belarus
Group 3: Kosovo, Malta, Faroe Islands, Azerbaijan
Group 4: Gibraltar, Liechtenstein, Macedonia, Armenia
Information from Press Association Sport was used in this report.