Striker Negredo put the world champions ahead in the 34th minute and added a second three minutes later before a sweetly-struck Xavi free-kick gave the home side a 3-0 lead at half-time.
A rare goal from full-back Sergio Ramos and two more from Spain's all-time top scorer Villa, his 48th and 49th for his country, completed the rout.
The victory against the tiny principality, with a population of 35,000 compared to Spain's 47 million, made it six wins out of six in Group I for Vicente del Bosque's side and put them eight points clear of second-placed Czech Republic.
"We struggled a bit during the first half hour but things improved as the game went on and I was lucky enough to score," Villa said in an interview with Spanish television.
"Now we have a lot of time to think about it [Euro 2012]," he added. "I think it's going to be important that we managed to qualify so early."
On a warm evening in Logrono, capital of Spain's La Rioja wine region, Del Bosque responded to a slew of injuries to defenders by deploying midfielder Sergio Busquets as a centre-back alongside Raul Albiol.
He left striker Fernando Torres out of the squad entirely and former Arsenal midfielder Cesc Fabregas on the bench and gave Negredo a start up front with Villa and Torres's Chelsea team-mate Juan Mata.
Villa made it 5-0 in the 59th minute when he swept home Mata's clever centre and grabbed a second and Spain's sixth with just over 10 minutes left with a volleyed finish from a Xabi Alonso free-kick.
"We are pleased but also perhaps a bit sad because there were some players who could not join in today," Del Bosque told Spanish television.
