Her third studio album, Chamber Music Society (2010), was a commercial success, charting at number 34 on the Billboard 200, and resulting in Spalding winning her first Grammy Award for Best New Artist.

Her subsequent sixth studio record, 12 Little Spells, was released in 2019, and peaked at number one on Billboard's Top Jazz Albums.

[11] Spalding herself credited watching classical cellist Yo-Yo Ma perform on an episode of Mister Rogers' Neighborhood as an integral part of her childhood, and it inspired her to pursue music.

[13] By the time Spalding was five, she had taught herself to play the violin and began performing professionally with the Chamber Music Society of Oregon.

"[18] Spalding also played oboe and clarinet in her youth[13][19] before discovering the double bass while attending The Northwest Academy, a performing arts high school to which she had won a scholarship.

[20] One of the seasoned musicians with whom she played invited her to join the band's rehearsals, which led to regular performances spanning almost a year.

[13] She decided to apply to Berklee College of Music on the encouragement of her bass teacher, and did well enough in her audition to receive a full scholarship.

[25][26] In spite of the scholarship, Spalding found meeting living expenses a challenge, so her friends arranged a benefit concert that paid her airfare.

[15][20] Spalding's savings did not last long and she considered leaving music to study political science,[25] a move jazz guitarist and composer Pat Metheny discouraged.

Gary Burton, Executive Vice President at Berklee, said in 2004 that Spalding had "a great time feel, she can confidently read the most complicated compositions, and she communicates her upbeat personality in everything she plays.

[15] Ratliff wrote in 2008 that one of Spalding's central gifts is "a light, fizzy, optimistic drive that's in her melodic bass playing and her elastic, small-voiced singing," but that "the music is missing a crucial measure of modesty.

"[32] He added, "It's an attempt at bringing this crisscrossing [of Stevie Wonder and Wayne Shorter] to a new level of definition and power, but its vamps and grooves are a little obvious, and it pushes her first as a singer-songwriter, which isn't her primary strength.

"[32] Pat Metheny said in 2008 it was immediately obvious "that she had a lot to say [...] she has that rare 'x' factor of being able to transmit a certain personal kind of vision and energy that is all her own.

[15] In 2008, Spalding recalled the tour as educational, helping her learn to accompany a vocalist and also how to sustain energy and interest playing the same material nightly.

[23] Ed Morales from PopMatters wrote that Esperanza is "a sprawling collage of jazz fusion, Brazilian, and even a touch of hip-hop.

"[35] Siddhartha Mitter wrote in The Boston Globe that Spalding's singing was noticeably different in Esperanza, making it more mainstream and attractive to a broader audience.

She closed the show with a number along with bass artists Brian Bromberg and Sean O'Bryan Smith, who also performed earlier that day.

Commenting on the album, NPR Music's Patrick Jarenwattananon wrote that, "the finished product certainly exudes a level of sophisticated intimacy, as if best experienced with a small gathering in a quiet, wood-paneled room.

[49] In February 2012, Spalding performed at the 84th Academy Awards, singing the Louis Armstrong standard "What a Wonderful World", alongside the Southern California Children's Chorus to accompany the video montage that celebrated the film industry greats who died in 2011 and early 2012.

[44] In November 2013, Spalding released a single "We Are America" to protest the Guantánamo prison camps, with cameo performances by Stevie Wonder and Harry Belafonte.

[57] On the album, Spalding sings through the alter ego of Emily (which is her middle name and childhood moniker), who she claims is a personification of a newfound innocence and authenticity to her composition.

[58] The album and corresponding tour featured musicians Matthew Stevens on guitar, Justin Tyson and Karriem Riggins on drums.

Spalding described the album's experimental structure as a result of her gradual distancing from the title of an "artist", gravitating towards a concept-driven identity.

"[35] Spalding, who has expressed a desire to be judged for her musicianship rather than sex appeal, believes that in general, female musicians should try and present themselves in a strictly professional manner.

[86] On September 4, 2018, Spalding performed a benefit for Bienestar, a local housing and outreach non-profit based in Hillsboro, Oregon.

[87] Several weeks later, she appeared with Herbie Hancock at the Lions of Justice Festival, sponsored by Soka Gakkai International, to support the respect and dignified treatment of all people.

She cited a lack of motivation amongst Harvard administrators to incorporate her changes to the curriculums she taught, as well as their unwillingness to redistribute some of its subjugated land to create a safe space for artists of color.