From 1983 to 1988, Sarandos managed eight Retail video stores in the "Arizona Video Cassettes West" chain. In 1988 Sarandos became Western Regional Director of Sales and Operations for one of the largest video distributors in the United States, East Texas Distributors (ETD). Until March 2000, Sarandos was Vice President of Product and Merchandising for the almost 500 store chain, Video City/West Coast Video. While at West Coast Video he was responsible for negotiating revenue deals to migrate from the company from the VHS format into the DVD format.

After meeting Netflix CEO Reed Hastings in 1999, Sarandos joined Netflix in 2000. He serves as its Chief Content Officer.

Sarandos married Michelle Sarandos, his first wife, with whom he had two children, Sarah and Tony. In 2009, Sarandos married former United States Ambassador to the Bahamas (2009-2011), Nicole Avant, the daughter of former Motown Chairman Clarence Avant. Producer Lawrence Bender introduced Sarandos to Avant. The couple live in the Hancock Park neighborhood of Los Angeles, after previously living in Avant's home town of Beverly Hills, California. In 2013, the couple purchased a beach house formerly owned by David Spade in Malibu, California. Sarandos has said he is Catholic.

Sarandos was responsible for initiating the first round of original programming at Netflix, starting with Lilyhammer, and then continuing with the breakout David Fincher series starring Kevin Spacey, House of Cards. Beginning with House of Cards, which was bought for $100 million in a March 2011 deal, Sarandos created the model where Netflix purchases multiple seasons of shows without pilot orders. Sarandos sees the focus as being on subscriber growth as a reflection of revenue health over ratings, especially because the ad-supported model doesn't apply to Netflix.

Sarandos and his wife, Nicole Avant, held a fundraiser for President Barack Obama's 2012 campaign in Southern California in 2009, and raised over $700,000 for the Democratic candidate.

Sarandos uses algorithms at Netflix to predict what programs viewers will want to watch prior to producing them. His personal algorithm focuses on 30% judgement (as a highest priority), with 70% focused on a base of data. He also said that the focus is on the audience, and that there is no programming grid – or appointment linear-based television – that is typically used by traditional TV networks. Barometers of success are if the audience completes watching the show, the timeframe within which they finish watching a series if there is social media buzz by critics and fans. Sarandos said that the preference is for show to run for multiple seasons and build a fan base. Sarandos believes the model allows the viewer to be in control, and to watch only the content they enjoy. The more serialized the show is, the longer the revenue stream. Sarandos sees cost per hour basis as greater the more total run time there is across the lifetime of a show, as it is often not cost savings to produce less original content once production is underway.

Sarandos set up a multi-picture deal with Adam Sandler, which was met with criticism. In defense, Sarandos said that the numbers make sense, something he characterizes as "data-influenced intuition," and that Sandler has a global appeal. Sarandos characterized Sandler's 2015 film The Ridiculous 6 as successful, saying it garnered the highest number of Netflix viewers streaming a film within the first 30 days of its release.

During the 2016 Television Critics Association presentation, Sarandos said he expects the amount Netflix spends on original programming to rise considerably. In terms of volume, Sarandos said that Netflix will be showing over 600 hours of original programming in 2016.