Rodrigo Moreno, Isco and Thiago Alcantara scored three goals in 11 minutes to set up a comprehensive win which was topped off with news from Rome that Italy had been held to a 1-1 draw by Macedonia, clinching Spain's spot in Russian Federation as Group G winners.
The run in to the game has been marked by the controversy over Barcelona defender Gerard Pique's views over the recent Catalan independence referendum and the insults he received while training in Madrid.
Julen Lopetegui's men approached the contest in Alicante knowing it would qualify for the finals in Russian Federation by bettering Italy's 1-1 result against Macedonia.
"There's still one match left and then we'll think about the play-offs".
"We did our part and with the Italy result it ended up being enough".
Serbia got off to the ideal start when Luka Milivojevic gave them an 11th minute lead. Brilliant performances of the Spanish team brought them an easy 3 points for the victory with a score of 3: 0, as well as the opportunity to grab a single line. Tom Lawrence scored for the Welsh side with Arsenal's Aaron Ramsey the provider.
Daryl Murphy scored both first-half goal as Ireland recorded a 2-0 victory over Moldova, to set up a fascinating final round clash against Wales.
"All we can do is work hard and take care of our business".
"As a Spaniard, I don't like what's happening, but let's hope it all gets resolved quickly and we can get back to living in a free democracy and enjoying sports, which is what makes us all happy".
Iceland look set to return to the world stage after unexpectedly reaching the quarter-finals at the European Championships past year.
Croatia face a tough last game away to Ukraine, who can still qualify themselves after a Leart Paqarada own goal and a Andriy Yarmolenko effort saw them win 2-0 in Kosovo to join the Croats on 17 points.