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 BRILLIANCE
The home side needed a trademark defence-splitting pass from playmaker Xavi in the 34th minute to break the deadlock after a well-organised Liechtenstein had frustrated the home side for the first half hour.
The Barcelona midfielder lofted the ball to Negredo, who controlled it on his chest, let it bounce once and lashed it past Liechtenstein goalkeeper Peter Jehle.
The Sevilla striker made it 2-0 three minutes later thanks to a piece of Villa brilliance.
Andres Iniesta picked out his Barca team-mate in the area and instead of shooting Villa backheeled the ball to Negredo who poked it into the far corner of the net.
Xavi stepped up with a sweetly-struck free-kick on the stroke of half-time and full-back Ramos sidefooted home an Iniesta cross seven minutes after the break.
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.
