Adam Lallana was on the scoresheet for the third time in as many games for England on Tuesday night, though later went off injured, as Liverpool's internationals played their final fixtures of the break.
Jordan Henderson again captained the Three Lions in the absence of Wayne Rooney, laying on Jamie Vardy's goal with a pinpoint cross - although two late Spain goals earned a 2-2 draw at Wembley Stadium. Nathaniel Clyne also played at right-back.
Lallana broke the deadlock after just nine minutes, beating former Liverpool goalkeeper Pepe Reina from the spot after Vardy was tripped by the Spanish shot-stopper.
That was his third in three games for his country, after going 26 games without a goal befor that, but his evening was ended less than 20 minutes later, when an apparent muscle injury forced the in-form attacking midfielder off the pitch.
And while Leicester City striker Vardy made it 2-0 on 48 minutes, Gareth Southgate's side couldn't see out his four-game spell as interim manager on a high.
Another former Liverpool player, Iago Aspas, cut the deficit to one with a minute of normal time remaining - firing a wonderful effort in off the post - before Isco fired through the legs of substitute goalkeeper Tom Heaton in the 96th minute to earn a draw.
Daniel Sturridge, who scored last week in England's win over Scotland, wasn't involved.
The result will be the least of the worries for Liverpool supporters, who will hope that Lallana, who will be sent for scans to assess his problem, can recover quickly.
The Reds visit the midfielder's former side Southampton this weekend, though the 28-year-old is a major doubt as it stands.
Meanwhile Henderson and Clyne both lasted the full 90 minutes at Wembley, the Liverpool skipper playing 180 minutes in less than a week over the course of the international break.
Afterwards, he admitted that England were "devastated" to let slip of the win, adding it was "very disappointing" to lose the game so late, particularly as they felt they "should have won."
Brazil duo Philippe Coutinho and Roberto Firmino return to Merseyside after an incredibly positive break, particularly for the former.
Coutinho featured for 86 minutes in the Selecao's 2-0 World Cup qualifying win over Peru in Lima in the early hours of Wednesday morning UK time.
That followed on from a fine display in a 3-0 win over Argentina in another qualifier last week, with Coutinho ending the calendar year as his country's joint-top goalscorer with five goals though he was not on the scoresheet in Peru.
Coutinho plays 86 minutes in another Brazil win
That tally betters even Barcelona's Neymar, with Gabriel Jesus - who is due to join Manchester City in January - Coutinho's only countryman to have also scored five goals in 2016.
Firmino, meanwhile, remained an unused substitute. He also played only the final eight minutes of the win over rivals Argentina and so - bar the fatigue of a 6,000-mile trip back to Liverpool - should be relatively fresh and fit for Saturday's clash with Southampton.
Coutinho, meanwhile, is likely to be subject to fitness tests having played 170 minutes of football for his country - helping them to six successive qualifying wins for the first time in 47 years and standing them in pole position to progress to the 2018 finals in Russia.
Earlier this week, centre-back Ragnar Klavan endured a forgettable evening as Estonia captain - losing 8-1 to Belgium in Brussels and scoring an own goal.
Wijnaldum wins but Klavan suffers heavy defeat
The Red Devils maintained their perfect qualifying record, although Klavan's teammates Simon Mignolet and Divock Origi remained unused substitutes.
Elsewhere on the same night, midfielder Georginio Wijnaldum played the full 90 minutes as the Netherlands beat Luxembourg 3-1 in a qualifier away from home.
The result means they are second place in Group A after four games, three points off leaders France.
Alexander-Arnold and Woodburn both in the goals for U19s
That secured their progression to the Elite Round of qualifying for the U19 European Championship, although fellow Academy starlet Ben Woodburn missed out with Wales Under-19s.
Though they thrashed Luxembourg 6-2, and the 17-year-old scored two - including a fine free-kick - they missed out due to an inferior goal difference.