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.”

Ben Ratliff wrote in The New York Times in 2006 that Spalding’s voice is “light and high, up in Blossom Dearie’s pitch range, and [that] she can sing quietly, almost in a daydream” and that Spalding “invents her own feminine space, a different sound from top to bottom.” Spalding was the 2005 recipient of the Boston Jazz Society scholarship for outstanding musicianship. Almost immediately after graduation from college later the same year, Spalding was hired by Berklee College of Music, becoming one of the youngest instructors in the institution’s history, at age 20. As a teacher, Spalding tries to help her students focus their practice through a practice journal, which can help them recognize their strengths and what they need to pursue.

Her debut album, Junjo, was released in April 2006 by Ayva Music. It was created to display the dynamic that she felt among her trio. Though Junjo was released solely under her name, Spalding considers it a group effort.

When asked in 2008 why she plays the bass instead of some other instrument, Spalding said that it was not a choice, but the bass “had its own arc” and resonated with her. Spalding has said that, for her, discovering the bass was like “waking up one day and realizing you’re in love with a co-worker.” By the time she randomly picked up the bass in music class and began experimenting with it, she had grown bored with her other instruments. Her band teacher showed her a blues line for the bass that she later used to secure her first gig. After that, she went in to play the bass daily and gradually fell in love.

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.” 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.”

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.” Andrés Quinteros wrote in the Argentinian periodical 26Noticias in 2008 that Spalding is one of the greatest new talents on the jazz scene today. Patti Austin hired Spalding to tour with her internationally after Spalding’s first semester at Berklee, where Spalding supported the singer on the Ella Fitzgerald tribute tour “For Ella”.

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. She continued to perform with Austin periodically for three years. During the same period, while at Berklee, Spalding studied under saxophonist Joe Lovano, before eventually touring with him. They began as a trio, expanding into a quartet before joining quintet US5 and traveling across the United States from New York to California. As of 2008, she was also in the process of developing several courses for students at Berklee, including one learning harmony and theory through transcribing. Due to touring commitments, Spalding stopped giving classes at Berklee. She lives in New York and Austin, Texas.

Siddhartha Mitter wrote in The Boston Globe in 2008 that Spalding’s singing was a noticeable difference in Esperanza, making it more mainstream and attractive to a broader audience.

In December 2009 at the Nobel Peace Prize ceremonies, Spalding performed at Oslo City Hall in honor of the 2009 Laureate U.S. President Barack Obama, and again at the Nobel Peace Prize Concert the following day. She was personally selected by Obama, as per the tradition of one laureate-invited-artist to perform.

On February 7, 2010, Spalding became the most searched person and second most searched item on Google Search as a result of her appearance the previous evening on the PBS television program Austin City Limits.

Esperanza is Spalding’s second studio album. After Spalding’s Grammy win in February 2011, the album entered the Billboard 200 at 138. With Esperanza, Spalding’s material was meant to be more reflective of herself as an artist, with musicians selected to best present that material. Ed Morales wrote in PopMatters on June 23, 2008, that Esperanza is “a sprawling collage of jazz fusion, Brazilian, and even a touch of hip-hop.”

In November 2011, Spalding won “Jazz Artist of the Year” at the Boston Music Awards.

Spalding collaborated with Tineke Postma on the track “Leave Me a Place Underground” from the album The Dawn of Light in 2011. She also collaborated with Terri Lyne Carrington on the album The Mosaic Project, where she features on the track “Crayola”. Spalding also sang a duet with Nicholas Payton on the track “Freesia” from the 2011 album Bitches of Renaissance.

Chamber Music Society is the third album by Spalding. After her surprise Grammy win, the album re-entered the Billboard 200 at number 34 with sales of 18,000. A video was made for the song “Little Fly”. The song is a poem by William Blake set to music by Spalding. A vinyl version of the album was released in February 2011. 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.”

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.

Radio Music Society is Spalding’s fourth studio album, released by Heads Up International in March 2012. Spalding hoped this album would showcase jazz musicians in an accessible manner suitable for mainstream radio, while incorporating her own musical compositions with covers of such artists as the Beach Boys and Wayne Shorter.

During her 2012 tour, Spalding donated a portion of proceeds from merchandise sales to the non-profit organization Free the Slaves. The organization, based in Washington, D.C., works to combat human trafficking around the world. In 2013, she performed a benefit for the American Music Program Pacific Crest Jazz Orchestra, a music program founded by her mentor, Thara Memory.

Spalding also made guest appearances during this time, appearing on Janelle Monáe’s 2013 album, The Electric Lady, on the track “Dorothy Dandridge Eyes”. She also sang a jazz duet on Bruno Mars’ album, Unorthodox Jukebox, called “Old & Crazy”. 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. In 2015, she appeared on the NOVA production The Great Math Mystery, talking about the connection between music and mathematics.

In March 2016, Spalding released her fifth studio album, Emily’s D+Evolution, a concept album featuring a funk rock sound. The album was co-produced by Spalding and longtime David Bowie collaborator Tony Visconti. On the album, Spalding sings through the alter ego of Emily, which is her middle name. In an interview, Spalding stated that Emily “is a spirit, or a being, or an aspect who I met, or became aware of. I recognize that my job…is to be her arms and ears and voice and body”. The album and corresponding tour featured musicians Matthew Stevens on guitar, Justin Tyson and Karriem Riggins on drums, and Emily Elbert, Corey King, and Nadia Washington on vocals.

During her time as a student at Berklee she began dating fellow student and jazz trumpeter, Christian Scott. They were in a relationship for 4 years. In a 2016 interview, Spalding stated she had residences in Brooklyn, New York, and Hillsboro, Oregon, the latter being where her family resides. She is a practitioner of Nichiren Buddhism.

In July 2017, Spalding was appointed a Professor of the Practice of Music at Harvard University. Five months later, in December, Spalding released Exposure, which is her sixth studio album. For this project, she embarked on a creative experiment beginning on September 12, 2017, setting out to create the album from start to finish in 77 consecutive hours, while streaming the whole creative process live on Facebook. Once completed, she released 7,777 limited edition recordings of the album. The packaging of the physical album included a piece of the original notepaper Esperanza used to write the lyrics and music, allowing those who witnessed the process to own a piece of the creation itself, directly from the source. About the experiment, Spalding stated that it being live forced her to be more creative, because there was no option to return to the same thing and try again. The same year, she appeared in the film Love Beats Rhymes in 2017.

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

From October 7 to October 18, 2018, Spalding released twelve tracks—one per day—that, in unity, form her seventh studio album, 12 Little Spells. Each “spell” was accompanied by a music video released on her YouTube channel and correlates to a singular body part. 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. On January 27, 2020 the album won the Grammy Award for Best Jazz Vocal Album.