Robert Moreno's side already had qualification and top spot in Group F secured heading into their final fixture and followed up a 7-0 demolition of Malta with another dominant display at the Wanda Metropolitano on Monday.
With the excellent Santi Cazorla having already hit the crossbar, Fabian Ruiz opened the scoring in the eighth minute. Gerard Moreno's double then put Spain out of sight.
Adrian Rus' own goal completed the first-half scoring, with substitute Mikel Oyarzabal picking out the bottom-left corner in the 91st minute to complete the rout.
Jose Gaya's foul saw the hosts have a goal disallowed in the fifth minute, before Cazorla rattled the bar with a brilliant strike from 18 yards.
Spain's dominance swiftly paid dividends, though - Fabian calmly side-footing home his first international goal after Ciprian Tatarusanu failed to hold Dani Carvajal's effort.
Romania would have been level if not for Kepa Arrizabalaga's save from George Puscas, and Spain made their goalkeeper's work count when Gerard headed in from Cazorla's exquisite first-time cross.
Cazorla was involved again when Gerard doubled his tally, playing a neat pass into Gaya, who crossed for the Villarreal forward to tuck in.
There was still time for Romania's first half to get worse - Rus diverting Gerard's cutback beyond Tatarusanu in the 45th minute.
Sergio Ramos looked set to make it 5-0 shortly after the break, only for Spain's captain to volley over from close range.
Alvaro Morata seemed to have been forced wide moments later but managed to dig out an effort that clipped away off the post in the 55th minute.
Spain's efforts to get a fifth were finally rewarded in stoppage time – Oyarzabal unleashing a crisp strike on the turn to round off La Roja's qualification in fitting fashion.
What does it mean? Sparkling Spain look in good shape
Moreno has picked up seamlessly where former coach Luis Enrique left off and - after a dismal World Cup campaign - Spain, with a rejuvenated squad, are sure to be contenders for the top prize next year.
Evergreen Cazorla shines bright
Cazorla's resurgence for Spain is a wonderful story and at this rate the midfielder - who will be 35 by the time the finals roll around - could well be one of Spain's chief creators at Euro 2020.
The former Arsenal playmaker was desperately unlucky not to open the scoring early on, before teeing up Spain's second with a delightful cross and playing a key part in La Roja's third.
Hapless Romania ravaged at the back
Romania's capital Bucharest is a host city for Euro 2020, but unless Cosmin Contra's side display more resilience in defence than they did on Monday, they will have little hope of making it through the play-offs.
While Spain will begin preparations for Euro 2020 with friendlies in March, Romania will discover their play-off opponents on Friday.