After winning the first 13 fights of his career all in his native
Dominican Republic, De Los Santos made his U.S. debut at T-Mobile Arena in Las Vegas, Nevada. He faced unbeaten American William Foster III. Despite starting off strong, Foster turned the fight around and hurt De Los Santos in the final round. Two judges scored the fight in Foster's favor, handing De Los Santos his first defeat by split decision. De Los Santos rebounded with a second-round stoppage against unbeaten Luis Acosta. He then faced highly touted unbeaten
José Valenzuela on the undercard of
Andy Ruiz vs.
Luis Ortiz. De Los Santos recovered from a first-round knockdown to knock Valenzuela down in the second and third rounds for a shock third-round stoppage win.
De Los Santos vs Stevenson After
Devin Haney announced he was vacating his belts, De Los Santos faced two-weight world champion
Shakur Stevenson for the
WBC lightweight title on November 16, 2023. In what was a remarkably inactive fight, De Los Santos lost by unanimous decision, resulting in Stevenson becoming a three-weight world champion.
Canceled Bout vs. Keyshawn Davis After more than a year of inactivity, De Los Santos was scheduled to face
WBO lightweight champion Keyshawn Davis at the Scope Arena in
Norfolk,
Virginia, on June 7, 2025. After failing to make the correct weight limit, Davis was stripped of the title, meaning only De Los Santos was eligible to win it. Subsequently, the two sides entered a lengthy negotiation in an effort to keep the main event intact. The fight was ultimately canceled after the two sides couldn't come to an agreement.{{Cite web |last=Hale |first=Andreas |date=2025-06-06 |title=Keyshawn Davis' fight with Edwin De Los Santos called off ==Professional boxing record==