Scotland hopes ruined by Silva and Villa
The Scots would have clinched a play-off berth by beating the world and European champions, who had already reached the finals in Ukraine and Poland, but second spot went instead to Czech Republic who triumphed 4-1 in Lithuania.
Spain went ahead in the sixth minute when Villa sent debutant full-back Jordi Alba clear down the left and he crossed for Silva to sweep a first-time shot past keeper Allan McGregor.
Manchester City playmaker Silva made it 2-0 shortly before half-time before laying the ball off in the 54th minute for Villa to grab his 50th goal on his 80th appearance.
Substitute David Goodwillie scored a consolation for the Scots from the penalty spot in the 66th minute after Craig Mackail-Smith had been hauled down by goalkeeper Victor Valdes.
Valdes was making a rare start in place of captain Iker Casillas as coach Vicente del Bosque gave some of his second-string players a runout.
"As you can see we have a lot of options," Del Bosque told a news conference. "It's healthy for the group getting everyone involved and having everyone feel useful.
"The season is very long and hopefully everyone will arrive at the European Championship in their best shape."
Spain's victory, their 14th in a row in competitive games since losing 1-0 to Switzerland at the World Cup finals in South Africa last year, meant they completed a second consecutive perfect qualifying campaign with eight wins out of eight.
They also won all 10 of their matches to make it through to the 2010 World Cup.
Scotland have not qualified for a major tournament since the 1998 World Cup in France.
They struggled to make an impression on the dominant Spanish until captain Darren Fletcher threatened in the 34th minute with a fine half volley that whistled narrowly over the crossbar.
The visitors made a better fist of things in the second period and the penalty was a just reward for their tireless chasing and harrying on a sweltering night in Alicante.
"Tonight was a tall order but Spain were at the top of their game," said coach Craig Levein. "I am disappointed we didn't get anything from the game but in keeping with the second half of the campaign I see a lot of positives.
"I am enjoying my job. This was a fantastic occasion tonight and being manager of the Scottish national team is something I am extremely proud of."