Heavyweights Spain qualified for the 2018 World Cup with a routine 3-0 home win over Albania, but Serbia must wait to seal to their place following a 3-2 loss in Austria.
Rodrigo, Isco and Thiago Alcantara all scored inside the first 30 minutes in Alicante as the 2010 world champions locked up top spot in Group G as Italy were surprisingly held to a 1-1 draw by Macedonia in Turin.
Barcelona defender Gerard Pique was greeted with a mixture of jeers and applause on his 92nd international appearance just days after voting in a referendum on Catalan independence deemed illegal by the Spanish government and blighted by police violence.
"We had to concentrate solely on football," coach Julen Lopetegui told Spanish TV station Teledeporte.
"It has been a difficult, complicated week and fortunately we managed to do that in a very, very good first 30 minutes."
Four-time World Cup winners Italy are destined for the November play-offs after Macedonian substitute Aleksandar Trajkovski's 77th-minute equaliser cancelled out a first-half goal by veteran defender Giorgio Chiellini.
"There's still one match left and then we'll think about the play-offs. We hope to get some players back," said Italy coach Gian Piero Ventura, whose squad has been depleted by a raft of injuries.
Serbia missed out on a chance to wrap up qualification from Group D with a match to spare as Louis Schaub struck a minute from time to give Austria victory in Vienna.
Serbia, who could have sealed a spot in Russia with victory, led through an early Luka Milivojevic goal but fell behind as Austria replied through efforts from Guido Burgstaller and Marko Arnautovic.
Manchester United midfielder Nemanja Matic had levelled on 83 minutes before Schaub's winner, but Serbia can still advance by defeating Georgia in their final qualifier in Belgrade on Monday.
Tom Lawrence scored his first international goal to earn Wales a vital 1-0 victory in Georgia and keep them firmly in the hunt for a finals berth.
The Derby County forward rifled in the winner four minutes after half-time in Tbilisi as Chris Coleman's team stayed a point clear of third-placed Republic of Ireland.
The Irish brushed Moldova aside 2-0 in Dublin through a first-half brace from Daryl Murphy and now face Wales at home in a final-round showdown with first place in the group still in play.
"All we can do is work hard and take care of our business. We have a huge test on Monday night against the Republic of Ireland. We have a game plan and we will see where it takes us," Coleman told Sky Sports.
Serbia head the section on 18 points with Wales, aiming to reach the World Cup for the first time since 1958, second on 17 and Ireland another point further back.
Iceland took a huge step towards a maiden World Cup appearance with an impressive 3-0 win over Turkey in Eskisehir that leaves the hosts all but out of the running.
Johann Gudmundsson, Birkir Bjarnason and Kari Arnason scored as Iceland pulled two points clear of Croatia at the top of Group I after the latter were held to a disappointing 1-1 draw at home to eliminated Finland.
Ukraine are level on 17 points with Croatia following a 2-0 win away to Kosovo and host the Croats in Kiev on Monday.
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