The world champions had been chasing an 11th straight victory under Luis de la Fuente but were forced to recover after Ivan Perisic put Croatia ahead in the 17th minute. The 37-year-old headed home to give Croatia a lead following their heavy 7-0 defeat by England in their previous Nations League outing.
Croatia delivered a far more competitive display this time and were applauded by the home supporters at the interval. Spain, however, emerged after the break with greater control and levelled in the 61st minute.
Dani Olmo took advantage of a loose Croatian clearance before finding Merino, who made no mistake with the finish. Lamine Yamal then saw an attempt blocked as Spain pressed for the decisive goal.
Perisic came close to restoring Croatia's advantage with a powerful strike that was saved, but his evening ended when he was shown a second yellow card for a foul on Marc Cucurella.
Spain made the numerical advantage count two minutes before full-time. Merino met a superb delivery from Martin Zubimendi and produced an excellent finish to complete the turnaround, with the pair also Arsenal team-mates.
"The players are ambitious," coach Luis de la Fuente said in the post-game news conference. "They are insatiable; they always want more. They don't conform with anything.
"This team has shown that, not only today, throughout this whole journey, that they go out to win matches. It's a wonderful attitude from a group of players who always want to give their best.
“We don't conform with being world champions, we want to keep improving every day, that's the aim.”
League B results:
Scotland 1-2 Slovenia
Ryan Christie opened the scoring for Scotland at Hampden Park, but Slovenia responded after the break. Goals from Aljosa Matko and Danijel Sturm secured a comeback victory for the visitors.
Switzerland 3-0 North Macedonia
Switzerland dominated in Lucerne with a comfortable win over North Macedonia. Fabian Rieder put the hosts ahead before second-half strikes from Johan Manzambi and Dan Ndoye wrapped up the points.
