While in the Las Vegas Academy, Smith adopted the stage name GoGo and joined an R&B group called Envy, who appeared during amateur night on Showtime at the Apollo and on the MTV’s The Cut (hosted by Lisa “Left Eye” Lopes of TLC). The group disbanded in 2000, and Smith continued to write songs for other artists before starting his solo career. The stage name Ne-Yo was coined by Big D Evans, a producer with whom Ne-Yo once worked, because Evans claimed that Ne-Yo sees music like the character Neo sees the Matrix.

After Envy disbanded in 2000, Columbia Records signed Ne-Yo, but the label dropped him before he could release his already-recorded first album. American singer Marques Houston happened to hear “That Girl”, which Ne-Yo had planned to release as his debut single from his then-unreleased album. Houston re-recorded the song and released it as a single for his 2003 album MH. The release of the song led to Ne-Yo being recognized as a top songwriter.

In 2005, Jesseca White, Ne-Yo’s girlfriend at the time, gave birth to a boy, naming him Chimere after Ne-Yo’s middle name. Though Ne-Yo believed he was the father, he later discovered the child was not his.

In early 2006, Ne-Yo released his debut album, In My Own Words, through Def Jam. Boosted by its popular second single “So Sick”, the album debuted at number one on Billboard 200, selling over 301,000 copies in its first week on sale. During the same week, the single had reached number one on the Billboard Hot 100. Later singles released were “When You’re Mad” and “Sexy Love”, which peaked at number 15 and number seven, respectively. The album has been certified platinum by the Recording Industry Association of America (RIAA) for a shipment of over one million units.

His second album, Because of You, was released on May 1, 2007, and, fueled by its lead single, debuted at number one on the Billboard 200, selling 251,000 copies in the United States; the feat gave Ne-Yo his second number-one album. The first single from the platinum-selling album was the title track, which peaked at the number-two spot. Despite the success of “Because of You”, later singles released charted lower and were unable to reach the Top 20. The album has been certified platinum by RIAA for a shipment of over one million units. In December 2007, Ne-Yo and the Goo Goo Dolls performed at a fund-raising concert for the then–presidential candidate Senator Barack Obama.

Ne-Yo ventured out to open his own recording studio, called Carrington House, in Atlanta, Georgia. He also had started his own production company, Compound Entertainment, in 2007, and has hired several producers and songwriters in hopes of turning it into a full-fledged record label. It successfully became a label, and artists such as RaVaughn, Paula Campbell, Sixx John, Adrienne Bailon and Shanell are now associated with Compound.

Ne-Yo’s third album, Year of the Gentleman, was released internationally on August 5, 2008. Speaking to noted UK R&B writer Pete Lewis of the award-winning Blues & Soul, Ne-Yo explained the thinking behind its title: “To me Year of the Gentleman is all about a persona, a swag and a charm. I made an assessment of the music business. And, in my personal opinion, the essence of the gentleman is absent right now. Everybody kinda looks the same, everybody’s kinda doing the same thing, everybody’s kinda rude and full of themselves. Whereas a gentleman is calm, courteous, kind, charming… So that title basically represents me trying to lead by example, and showing these cats what it is to be a gentleman in this business still.”

On August 12, 2008, the New Kids on the Block released “Single”, the second single from their fifth studio album, The Block, which is a duet with Ne-Yo. Ne-Yo included a solo version of the song on his album Year of the Gentleman.

In December 2008, Ne-Yo performed at the Kennedy Center Honors as part of the tribute to Barbra Streisand; he sang and danced to the song “Lover Come Back to Me”, which Streisand recorded on her second album in 1963.

In 2009, Billboard ranked him as the 57th Artist of the 2000s decade.

On September 2, 2009, Ne-Yo released greatest hits album Ne-Yo: The Collection in Japan. The album was also released with a limited edition CD+DVD edition complete with the music videos of singles. It debuted at number four on Japan’s Oricon weekly albums chart, selling 55,625 copies in the first week.

In January 2010, Ne-Yo was featured in a duet with singer Mariah Carey titled “Angels Cry”.

In June 2010, Ne-Yo released the single “Beautiful Monster”, which became Ne-Yo’s first number-one single on the UK Singles Chart. It peaked at number 53 on the Billboard Hot 100 chart.

On October 8, 2010, Ne-Yo performed some of his songs from the new album at P.C. Richard & Son Theater in New York City, an event hosted by iHeartRadio. Ne-Yo made an appearance at New York ComicCon to announce that he was collaborating with Stan Lee for a Libra Scale comic. Ne-Yo also met with fans for pictures and autographs in the Cultyard of the ComicCon. The second and third singles released from the album are “Champagne Life” and “One in a Million”, respectively.

Libra Scale was released on November 22, 2010. It received critical acclaim from music critics, but was a commercial disappointment, debuting at number nine on the US Billboard 200 chart, selling less than all of his previous three studio albums. Ne-Yo stated: “The album is based upon this short story which basically follows these three characters who are forced to choose between money-power-and-fame versus love. Which in turn is why I’ve called it ‘Libra Scale’. You know, its whole concept is based on that question of morality – that, if you weighed it all out on a libra scale, which one of those two options would you choose?”. Libra Scale sold 112,000 copies in its first week. In the United Kingdom, the album debuted at number 11 on the UK Albums Chart, while debuting at number one on the UK R&B Chart.

In 2010, he dueted with Mariah Carey on “Angel’s Cry”, a song for her cancelled album, Angels Advocate. Ne-Yo has also written songs for Celine Dion, Whitney Houston, Carrie Underwood, Anastacia, Ciara, Corbin Bleu, Enrique Iglesias, and Dima Bilan. He collaborated with Lindsay Lohan on her new material, having already finished “Bossy”, a pre-single for her new album Spirit in the Dark. In 2007, Ne-Yo confirmed that he had been contacted by producer will.i.am to work on what would have been Michael Jackson’s new album. However, at the time of Jackson’s death, Ne-Yo’s collaborations with him had yet to move past the writing stage. In an interview in 2010, Ne-Yo said that, since Jackson’s death, he had been confused as what to do with the songs, as he felt that selling them to another artist or even releasing the songs himself would be disrespectful to Jackson’s legacy. In 2009, he wrote “Truth (Saigo no Shinjitsu)” for w-inds., the Japanese pop group.

In June 2010, Ne-Yo told Ebony that he and his then-girlfriend, Monyetta Shaw, were expecting their first child together – a girl due early in 2011. Shaw gave birth early to daughter Madilyn Grace Smith on November 12, 2010, in Atlanta, Georgia. Announcing the birth, Ne-Yo said of his first child, “I’ve been in love before but this feels like nothing I’ve ever felt… like I’m in love for the first time.”

On February 25, 2011, while on his tour in the United Kingdom, he announced his new album would be called Love and Passion and would be released in September, but this was proven false as the title was tentative. American rapper Fabolous said in an interview that he is planning a collaboration album with Ne-Yo as well. Ne-Yo has also written songs for Mary J. Blige, JB, Beyoncé, Monica, Alexandra Burke, Cheryl Cole and Willow Smith’s upcoming albums. Ne-Yo starred in two motion pictures, the long-gestating George Lucas project Red Tails, released in early 2012, and Battle: Los Angeles, which was released in the United States on March 11, 2011. Ne-Yo has already finished writing songs for American singer and Roc Nation artist Alexis Jordan and her self-titled debut album as well as Jennifer Hudson for her second studio album, I Remember Me, which had a North American release on March 22, 2011. Ne-Yo appeared in the children’s preschool show The Fresh Beat Band and was one of the few artists not to cancel appearances in the wake of the 2011 Japan earthquake.

In 2011 Ne-Yo was approached by Cartoon Network to help create an animated series. Ne-Yo announced that the show would be titled I Heart Tuesday and that he had created it for his sister. He also stated that he wanted to avoid having the show resemble the anime art style of The Boondocks due to the potential cost of the show’s animation style.

In 2011, Ne-Yo appeared in an episode of The Fresh Beat Band as himself.

In September 2011, Ne-Yo revealed that he was expecting his second child with Monyetta Shaw. Shaw gave birth to a boy, Mason Evan Smith, on October 9, 2011.

In January 2012, it was reported that Ne-Yo, along with his label imprint Compound Entertainment, had moved from Def Jam Recordings to Motown Records. He was also appointed Senior Vice President of A&R of Motown, where he would serve “…as a producer and mentor to the label’s artists, as well as seeking out and signing new talent to the label.” Ne-Yo was slated to release his fifth studio album, R.E.D. (as in “Realizing Every Dream”), on September 18, 2012. The album was initially titled The Cracks in Mr. Perfect. The album’s first official single, “Lazy Love”, was released on June 12, 2012 and peaked at number forty-two on the US Hot R&B/Hip-Hop Songs chart. “Let Me Love You (Until You Learn to Love Yourself)”, co-written by Australian singer-songwriter Sia, was released as the second single on July 31, 2012. Because of Kevin McCall’s new album and the song Ne-Yo will be in, “Love Time”, was not yet released because he and his friend Chris Brown will make an appearance on Ne-Yo’s R.E.D. album in the song called “What I Do”, which they all will be involved in writing the beat says Ne-Yo, who was interviewed by TMZ in New York. “I expect this to be a banger in clubs for the slow songs and to get Ne-Yo his first top 10 song in years,” said Chris Brown, after a celebrity basketball game with Ne-Yo, Kevin Hart, and other celebrities in the month of July.

On August 29, 2012, Ne-Yo was one of the headliners alongside R&B recording artist Melanie Fiona, in the Summer Beats Concert Series, otherwise known as the MJ Birthday Concert, which was on what would have been the 54th birthday of the late American pop icon Michael Jackson which was sponsored by and live-streamed by Pepsi and Billboard. He performed a medley of hits, as well as performing “The Way You Make Me Feel”, “Smooth Criminal” and “I Just Can’t Stop Loving You” from Jackson’s best-selling 1987 album, Bad, in preparation for the reissue of Bad 25 on September 18, 2012. The concert took place at Gotham Hall in New York City. R.E.D. was released in the United Kingdom on November 5, and in North America on November 6, 2012. On December 8, 2012, Ne-Yo was the musical guest for Saturday Night Live with Jamie Foxx guest-hosting for that week.

In 2012, Ne-Yo was awarded the Hal David Starlight Award of the Songwriter’s Hall of Fame which honors gifted songwriters who are at an apex in their careers and are making a significant impact in the music industry via their original songs.

In March 2013, Ne-Yo collaborated with Akon on David Guetta’s single “Play Hard”, from his 2012 album Nothing but the Beat 2.0. He also collaborated with Jessica Sanchez on her single “Tonight” from her debut album Me, You & the Music. The single, along with the music video was released on March 21, 2013. In April, Ne-Yo and Cher Lloyd collaborated on their single “It’s All Good”, which eventually was featured on Fruttare commercials. Around the same time, he and Celine Dion recorded “Incredible” for Dion’s 2013 album Loved Me Back to Life. “Incredible” was released as a single in February 2014 and the music video premiered in June 2014.

On May 29, 2014, Ne-Yo announced his upcoming sixth studio album would be called Non-Fiction. That same day, he announced a new single, “Money Can’t Buy”. On September 16, 2014, the lead single from “Non Fiction” was sent to mainstream radio titled “She Knows” featuring Juicy J. A few months later, Ne-Yo announced that the new release date for Non-Fiction was January 27, 2015. The album included collaborations with Pitbull and Charisse Mills. The album peaked at number five on the Billboard 200 chart.

In July 2015, Ne-Yo collaborated with Dimitri Vegas & Like Mike on a new song for the Tomorrowland anthem titled “Higher Place”. In 2016, Ne-Yo collaborated with Yunel and J Alvarez for their single entitled “Sin Miedo”, released on November 12, 2016 and with Diamond Platnumz for their single entitled “Marry You”, released on February 2, 2017.

In September 2015, the singer announced that he and Crystal Renay Williams were engaged and expecting a child. They were married on February 20, 2016. Their son, Shaffer Chimere Smith, Jr., was born on March 15, 2016. Their second son, Roman Alexander-Raj Smith was born on June 14, 2018. In February 2020, Ne-Yo announced that he and Crystal Smith would end their marriage, and he withdrew his divorce case afterwards.

On May 8, 2017, Ne-Yo released a single “Earn Your Love” from his forthcoming seventh album, whilst announcing that the album is slated for a release in 2017. A new single, “Another Love Song” was released on May 30, 2017. In July 2017, he made a cameo in the comedy film Girls Trip, starring Queen Latifah, Jada Pinkett Smith and Regina Hall.

In August 2017, Ne-Yo announced he had adopted a vegan diet after viewing the documentary What the Health. In February 2019 he said in an interview that he had lost “like 30 pounds” and had also reversed his tendinitis since he became vegan, calling it “one of the best things he’s ever done”. His representative confirmed in March 2020 that he was no longer a vegan.

He starred as the Tin Man in NBC’s musical telecast adaptation of The Wiz alongside David Alan Grier, Elijah Kelley, Queen Latifah, Common, Amber Riley, Uzo Aduba and Mary J. Blige. The musical telecast premiered December 3, 2015 as a three-hour event. For his performance, he received a Critics’ Choice Award nomination for Best Supporting Actor in a Movie made for Television or Limited Series. In May 2018, he took part in the Celebrity Ninja Warrior special for Red Nose Day. He completed the course, resulting in a $30,000 donation.

In December 2018, he was the entertainment at 67th Miss Universe pageant where he performed during the final catwalk.

In 2019, in wake of the television documentary, Surviving R. Kelly, Ne-Yo confirmed his support for the Mute R. Kelly campaign, for the protection of his own daughter.

On March 27, 2020, Ne-Yo collaborated with Jamaican dancehall singer Charly Black for a new single, Over Again.