The LA Galaxy welcomed back Landon Donovan with a win as the New York Red Bulls were held in MLS.
Donovan, 34, came out of retirement and made his return on Sunday – 643 days after his previous MLS match.
He came off the bench with the Galaxy cruising at the StubHub Center thanks largely to Dos Santos.
Kevin Molino had put the visitors ahead, but the Galaxy equalised as Dos Santos tapped in a cross from Emmanuel Boateng.
Another cross from the left, this time from Jelle Van Damme, saw Alan Gordon put the hosts in front.
A Dos Santos penalty on the stroke of half-time had his team in control and the Mexican set up Robbie Keane for an easy fourth.
Brek Shea pulled a goal back late for Orlando, who are sixth in the Eastern Conference – while the Galaxy moved into second in the West.
The New York Red Bulls missed their chance to go top in the East after a dramatic 2-2 draw at home to DC United.
Goals from Gonzalo Veron and Bradley Wright-Phillips had the Red Bulls on track before the late drama.
A neat finish from Steve Birnbaum gave the visitors hope in the Atlantic Cup, before Lamar Neagle equalised with a scrappy 95th-minute goal.
The Red Bulls are second to Toronto in the East, while DC are just a point behind sixth-placed Orlando.