"Fox is finished. Fox that we have known for 20 years is over," Wolff said on "Squawk Box." "This represents kind of a cable blip. We're entering an entirely new era."
O'Reilly agreed to leave Fox News in April, nine months after Ailes was forced out. O'Reilly and Ailes deny the claims.
Fox News host Megyn Kelly, who accused Ailes of unwanted sexual advances, left the network in January and is now with NBC News.
Wolff, a Hollywood Reporter columnist, said the "unique chemistry" O'Reilly and Kelly had with their devoted prime-time audiences cannot be replicated.
"All that chemistry is gone because all those people are gone," said Wolff, whose 2008 book "The Man Who Owns the News: Inside the Secret World of Rupert Murdoch" is a biography of 21st Century Fox's executive chairman.
Ahead of Shine's resignation, conservative commentator Sean Hannity expressed support on Twitter for Shine with the hashtag #Istandwithbill.
Shine was at Fox News from the start, originally coming in as Hannity's producer in 1996.
"We will definitely lose Sean Hannity, if not in days in months," Wolff predicted.
The ratings have held up pretty well at Fox News since it was forced to shake up its prime-time lineup last month.
Tucker Carlson replaced Kelly at 8 p.m. ET and the popular ensemble show, "The Five," replaced O'Reilly at 9 p.m. ET.
Hannity stayed at 10 p.m. ET.
But Wolff thinks an O'Reilly-less lineup is "completely not sustainable," calling the troubles at Fox News "a wide open opportunity" for rivals who want to reach a right-leaning audience.
"All those ratings happened because [of] O'Reilly at 8 o'clock. You just have a fall off of his audience across the night. ... Now you start with a lower baseline," Wolff said. "We are just left with a network that has a significant penetration but no reason for people now to really watch it."
Wolff said the decisions to part ways with Shine, O'Reilly, and Ailes were driven by Murdoch's sons.