Negredo, who scored Spain's second in Friday's 2-1 win over Belarus and is looking a strong candidate for a regular place up front, clipped a volleyed Andres Iniesta centre into the net to put Spain ahead in the 26th minute.
The Manchester City forward scuffed a shot against the post five minutes before half-time before Mata, who had replaced Pedro moments earlier, pounced on a loose ball and cracked home from close range in the 61st.
It was a memorable night for local hero Iniesta, who hails from a small town around 40 kilometres from Albacete, and he was given a rapturous reception by the home fans.
Franck Ribery inspired France to a 3-0 win over Finland but they must now plan for next month's World Cup play-offs after missing out on automatic qualification with Spain sealing top spot in Group I.
France, 25th in the latest FIFA standings which will be updated on Thursday, are unlikely to be seeded in the play-off draw which takes place in Zurich on Monday.
[GROUP I: Final standings]
The hosts went ahead after eight minutes when Ribery, a hot candidate for the FIFA Ballon d'Or award after another impressive showing, unleashed a missile from the edge of the area that flew into the top corner.
France missed several clear chances but put the result beyond doubt in the 76th minute when Joona Toivio deflected Olivier Giroud's header into his own net.
Kerim Benzema, who ended a 15-game goal drought for France in last Friday's 6-0 hammering of Australia in a friendly, volleyed in from Ribery's fine pass to make it 3-0 three minutes from time.