Ronson has stated that she fell into DJing by chance. “I got a call one night from a club that I used to hang out at and they were like, ‘Do you want to DJ?'” Ronson remembered. “I was like, ‘No way,’ [but] my friends were like, ‘Come on, just do it.’ I was always in the club; [I figured I] might as well make money off it.” Ronson took the gig and she quickly started to make a name for herself and eventually DJing became a full-time job. Today she spins at some of the most high-profile gigs around the world. She has spun live for MTV’s New Year’s Eve show from the network’s studios in Times Square, as well as at the Super Bowl, Pan American Games, Sundance Film Festival, amfAR, Cannes Film Festival, AMA and VMA. She has played private events for celebrities like Stevie Wonder, Jimmy Kimmel, Nicole Richie, Lionel Richie, Jessica Simpson, Ellen DeGeneres, Natalie Portman, Lindsay Lohan, and Jay-Z.

Ronson was the official DJ for Hennessy (Hennessy Black) in 2011. In 2009, 2010 and 2014 Ronson designed her own set of sneakers for the company Supra. She appeared in a 2011 campaign for cult fashion label Boy London in collaboration with The Cobra Snake (Mark Hunter). She is or was a co-owner of the New York City nightclub The Plumm, along with actor Chris Noth and Noel Ashman, among others.

Ronson became the first rock act signed to Roc-A-Fella Records. In 2002, it was announced Duncan Sheik would be co-producing an album for Ronson that would be out in the spring. She released four songs on Roc-A-Fella Records: “Pull My Hair Out”, “Fool”, “If It’s Gonna Rain” and “Built This Way”, and wrote and recorded her first album, Red. “Built This Way” was featured in the movie Mean Girls starring Lindsay Lohan and Rachel McAdams. “Pull My Hair Out” was featured on the soundtrack of the movie The Woodsman starring Kevin Bacon and the song “Wanted”, by Rhymefest featuring Samantha Ronson, appeared in the movie Half Nelson. In 2004, she opened for JC Chasez on his Schizophrenic tour. However, inauspicious timing and the dissolution of the Roc-A-Fella Records led to her first album never being released.

In November 2011, Ronson released the album Chasing the Reds on her own label, Broken Toy Records. The album showcased her songwriting abilities, drawing inspiration from events in her life. In an interview with American Songwriter, she stated, “I grew up in the studio with songs. My stepdad wrote some pretty f—ing incredible songs. My brother [producer and musician Mark Ronson] made his records because he likes making songs. So, the standard was set pretty high for being true to what you want to do. I’m not just going to hand my song over to a producer; I want to be there every step of the way…I feel like when you’re doing what you love, instead of fitting yourself into somebody else’s box, that comes across”.

Guest stars appear on the album including Wale on “Summer of Sam”, Alex Greenwald of Phantom Planet on “Captain Jack” and Slash on the track “Love Song”. The album was produced by former Goudie guitarist Jimmy Messer, with Ronson herself sharing co producing credits. Her brother Mark produced one track, “Skyscrapers”, which was co-written by the siblings with Santigold.

In 2016, Ronson, Pete Nappi and Ethan Thompson formed the band Ocean Park Standoff.[22] The members first met at a songwriting session in 2014. Their debut single “Good News” was released on 7 October 2016, along with its B-side, “Photos & Liquor”. Ocean Park Standoff is going on a US tour starting in February 2017, and their debut EP was released on Hollywood Records on 3 March 2017.