In early 1998, Damon de Szegheo, record producer and owner of the Peterborough based independent record label Mime Radio, approached her about recording. de Szegheo had noticed her when she sang during a set change for a local stage production of Gone with the Wind. The product of their sessions was a self-titled promotional cassette, Serena (limited to a run of 100) and her first full-length CD, Falling Out, released in December 1999.

Ryder was later managed by Kellie Bonnici. Bonnici approached Ryder with an offer to help her after being moved by her performance at the 2001 Peterborough Folk Festival, where Ryder was awarded the Festival’s first “Emerging Artist” award. This award enabled Ryder and Bonnici to attend a regional music festival conference and make some initial connections. Bonnici worked with Ryder to release Live at the Market Hall and A Day in the Studio in 2002.

Ryder was invited by Erin Benjamin (then the president of the Ontario Council of Folk Festivals) to perform in Winnipeg at a regional music conference. There her manager, Bonnici, met the CBC radio host Avril Benoit during one of Ryder’s showcases. They later arranged an interview for Ryder on CBC’s Here and Now, which caught the attention of the musician Hawksley Workman and Sandy Pandya, who was then his manager. After initial meetings with Workman and Pandya, Ryder was invited to record on Workman’s Isadora label. Shortly thereafter, Ryder and Bonnici amicably parted ways, and Ryder began working with Pandya in 2004.

In 2005, Isadora Records released Live in Oz, a recording from Ryder’s tour of Australia, in limited numbers available only at live performances.

In 2005, backed by Workman and two other players, Ryder recorded her debut album with a major label, Unlikely Emergency. The album did well enough to earn Ryder a performance at the 2005 Canadian Songwriters Hall of Fame press conference, after which it was suggested she cover songs written by other Canadian musicians. Meanwhile, the poignant song “Just Another Day” got considerable airplay on various Canadian radio stations.

In November 2006, Ryder released her second album, If Your Memory Serves You Well, a collection of 12 covers of notable Canadian songs and three original songs. The tracks include Sylvia Tyson’s “You Were On My Mind”, Leonard Cohen’s “Sisters of Mercy”, Galt MacDermot’s “Good Morning Starshine” the Bob Dylan–Rick Danko collaboration “This Wheel’s on Fire”, and Paul Anka’s “It Doesn’t Matter Any More.”

The EP Told You in a Whispered Song, released on June 19, 2007, is an acoustic studio collection of several live tracks and new songs by Ryder. Touring in Canada, Ryder was part of Blast From The Beach in Prince Edward Island on July 21, 2007 headlined by Aerosmith and featuring other notable bands, including 54-40 and Cheap Trick. Touring in Australia that same year, Ryder appeared as a guest on SBS’s RocKwiz in March, where she displayed an authoritative knowledge of rock music, singing song segments in answer to questions presented to her; she also performed in the closing guest spot, with Lior.

In April 2008, Ryder found herself receiving the 2008 Juno Award for “Best New Artist of the Year” while on the label EMI. On November 11, 2008, Is It O.K., was released in Canada on EMI Canada and on Atlantic Records in the United States on February 11, 2009. The single “Little Bit of Red”, which won a Juno Award in 2010 for Best Video of the Year, was released on that album. As well, “All for Love”, which appears on Is It O.K. and the EP Sweeping the Ashes, was featured in an episode of ABC television’s Private Practice. In Canada, Is It O.K. won the Juno Award for Adult Alternative Album of the Year in 2009. In the United States, the album got a warm reaction and Ryder furthered her foray into the U.S. by recording the duet “You Can Always Come Home” with American Idol Jason Castro on his debut album.

In May 2009, Ryder appeared on Bruce Springsteen’s official website, covering his song “Racing in the Street”. The video was part of the “Hangin’ on E Street” feature of his website. That year, her song “Sing, Sing” was selected for Music Monday, a special event to highlight music education in Canada, for which nearly two million Canadian schoolchildren sang the song in class on May 5.

In July 2010, Ryder joined the lineup of Lilith Fair along with Sara Bareilles, Jill Hennessy, Emily Robinson, and Martie Maguire.

On February 19, 2011, Ryder toured with Melissa Etheridge across Canada. Ryder’s song “Broken Heart Sun” was performed as a duet with Etheridge, and a recording was released on her EP Live. Ryder performed “Broken Heart Sun” with Etheridge at the Juno Awards that same year.

In 2011, Ryder fell in love, and it inspired her for her fifth studio album, Harmony. Over 65 songs were written for the album; “[i]t feels like it’s the first time I’ve written …in love”, she said.

After writing more songs while in Los Angeles with Jerrod Bettis and Jon Levine, Ryder released Harmony on November 27, 2012. The first single “Stompa”, co-written with Bettis, was used in an episode of ABC television’s Grey’s Anatomy, quickly climbed the charts, and became certified platinum in January 2013. In the United States, less than two months after its release, it was at number 14 on the charts. In Canada, Ryder became the first Canadian artist to be number one on the CBC’s Radio 2 Top 20 chart, days after the release of Harmony. “Stompa” was played in four radio station formats: Modern Rock, Hot AC, Top 40 and Adult Contemporary.

Ryder performed at the opening night of Luminato Festival on June 14, 2013 in Toronto, Ontario. She also performed in Calgary, Alberta on July 6, 2013 as part of the Calgary Stampede. On July 17, 2013, Ryder made her late night show debut, performing “Stompa” on The Tonight Show with Jay Leno.

In 2014, Ryder performed O Canada for the 2014 NBA All-Star Game. She also provided vocals for the song “In The Morning” on the fifth studio album by Canadian rock band, The Trews.

In March 2014, Ryder co-hosted the Juno Awards, and won Artist of the Year and Songwriter of the Year.

In May 2015, Ryder recorded “Together We Are One”, the official theme song for the 2015 Pan American Games. The song reached #1 on the Radio 2 Top 20 the week of July 17, 2015. She performed at the Pan Am Games Closing Ceremony.

In August 2015, Ryder performed on CBC TV’s “Quietest Concert Ever on the Ocean Floor”, which took place on the ocean floor during low tide at Fundy National Park in New Brunswick, Canada. During this pre-recorded concert documentary (also available to stream on YouTube), she performed songs from her upcoming album titled Utopia. The televised broadcast of this concert was on September 25, 2015.

On June 24, 2016, Ryder released the single “Got Your Number” and dropped her sixth studio album Utopia on May 26, 2017, containing 17 songs. The EP Electric Love was released the same day for the U.S. and European markets but not in Canada. Utopia’s first single was “Electric Love.”

On March 9, 2018, Ryder’s song “Be the Ones” was chosen to be the official theme song for 2018 Arctic Winter Games.

On April 6, 2018, Ryder released her single “Famous” featuring Simon Ward of The Strumbellas for the US market. Co-written with Simon Wilcox and Simon Ward, “Famous” is a song about society being obsessed with social media and people trying to achieve fame solely for the sake of being famous.

On September 9, 2018, Ryder was invited for a duet with Brett Kissel at the Canadian Country Music Association (CCMA) Awards in Hamilton. The CCMA Awards was hosted by Shania Twain.

On September 23, 2018, Ryder started hosting her own radio program, The Serena Ryder Radio Show on CHFI-FM, which aired across Canada for eight weeks.

On August 11, 2018, Ryder was one of the artists invited to join Billy Talent for the #TorontoStrong benefit concert following the Danforth shooting on July 22, 2018.

On April 4, 2018 Ryder received the Margaret Trudeau Mental Health Advocacy Award for her work with mental health.

On September 12, 2019, Ryder and her longtime manager Sandy Pandya co-launched ArtHaus, a collaborative space and recording studio aiming to promote emerging talent.

On October 19, 2019 Ryder joined the roaster of artists who performed for the benefit concert Secret Path at Roy Thompson Hall. Secret Path is a recreation of the 2016 multimedia performance by the Tragically Hip’s lead singer Gord Downie on the story of Chanie Wenjack, a 12-year-old Ojibwe boy who died while escaping a residential school in 1966. The proceeds go to promote reconciliation.