Louis van Gaal's side are head and shoulders above their rivals in Group D and proved it again at the Amsterdam ArenA.
Rafael van der Vaart opened the scoring in the 11th minute, while after the break Van Persie struck twice, the second a penalty, and Jeremain Lens added a fourth in the last minute, as Holland extended their lead at the top of the pool to seven points.
While the hosts' spot in Brazil next year seems almost secure, Romania are scrapping for the play-off place and this defeat did not damage their hopes too much, leaving them a point off second-placed Hungary, who came from behind to draw 1-1 at home to Turkey.
The Dutch endured such a disappointing Euro 2012 campaign, but they have won all of their opening six qualifiers in the current campaign by at least two goals.
They also hit four past Romania in the reverse fixture back in October, winning 4-1, and needed only 11 minutes to find the net again tonight.
Van Persie's ball in from the right picked out Van der Vaart, who steered a low shot into the bottom corner from 18 yards.
The Hamburg midfielder was only starting because the groin injury Wesley Sneijder suffered in Friday's victory over Estonia had ruled him out of tonight's match.
Kevin Strootman fired wide of the left post as the hosts threatened again, but they were almost undone late in the first half.
Alexandru Bourceanu's inswinging corner caused problems for the Dutch defence and goalkeeper Kenneth Vermeer had to claw the ball away to prevent it from going in.
Van Persie tested Romania keeper Costel Pantilimon early in the second half and the Manchester United striker doubled the lead in the 55th minute.
Arjen Robben's left-wing cross picked out Van Persie at the near post and he directed his header high into the net.
Two became three nine minutes later when Florin Gardos' foul on Lens earned Holland a penalty.
Van Persie stepped up and placed the spot-kick low into the bottom right corner.
Knowing the fight for second could yet come down to goal difference, Romania pressed for a consolation and it almost arrived when Bogdan Stancu's shot from inside the area produced a fine save from the alert Vermeer.
Instead, with time almost up, they conceded a fourth.
Adam Maher's shot fell for Lens, who diverted the ball low into the net from close range to complete a job well done for the Dutch.