In 1998, Natalia was part of a girl trio called Twist. The group was unsuccessful and they split up the following year.

In 2003, she was nominated for a Latin Grammy in the Best New Artist category for her debut album. She was also the principal contributor to the soundtrack for the Mexican movie Amar te duele and contributed the song “Un Pato” for the movie Temporada de patos. Lafourcade was nominated for Rock New Artist at the 16th Lo Nuestro Awards, losing to fellow Mexican singer Alessandra Rosaldo.

In 2005, she released Casa, her second album, but this time as Natalia y La Forquetina, the name of her band. Produced mostly by Café Tacuba’s Emmanuel del Real, Casa presents a more mature, rock-oriented sound while retaining pop and bossa-nova influences on a few tracks, such as lead single “Ser Humano” (pop-rock) and its follow-up “Casa” (pop-bossa-nova). Aureo Baqueiro returned to produce the few tracks not produced by del Real.

In June 2006, after a tour through Mexico and parts of the U.S., on 2 June, Lafourcade announced she would leave La Forquetina to once again work as a solo artist. Natalia y la Forquetina’s final show was played on 18 August 2006 in San Luis Potosí. Following the group’s break-up, Casa won the Latin Grammy for Best Rock Album by a Duo or Group with Vocal in September.

Also in 2006, a documentary about the band, showing the group on the road and their travels, was aired on MTV Tr3s in the fall of 2007.

In 2008, she performed on Julieta Venegas’ MTV Unplugged album and DVD.

In 2009, she released the album Hu Hu Hu, a top 10 album in Mexico. The album was produced by Emmanuel del Real (who produced “Casa” in 2005), Marco Moreno and Ernesto García. It was nominated for Best female Pop Vocal Album at the 2009 Latin Grammy Awards (won by Laura Pausini) and Best Latin Pop album at the 2010 Grammy Awards (won by La Quinta Estación). Club Fonograma also named the album the second best of 2009, and the seventh best of the decade.

In 2011, Lafourcade won the Best New Producer of the Year award in the Indie-O Music Awards, for her work with Carla Morrison’s Mientras tu dormías album.

Natalia Lafourcade has also appeared on other songs with various other artists. These include Liquits’ “Jardin”, Kalimba’s “Dia de Suerte”, Control Machete’s “El Apostador”, and Reik’s rendition of a Lafourcade song “Amarte Duele”. Also she along with her former band have appeared on various compilation disks with previously unreleased tracks such as “Y Todo Para Que” on Intocable’s X and on the Tin Tan tribute album, Viva Tin Tan, with the hit “Piel Canela”. In 2011, she made “Quisiera Saber”, a music video with Los Daniels.

In 2012, she released a tribute album to Agustín Lara called Mujer Divina.

Her next album, Hasta La Raíz, was released in March 2015. “Nunca Es Suficiente” (It’s Never Enough), the first single off the album, was released on 10 February. The track “Hasta La Raíz” was No. 5 of the Viral 50 Global Spotify Chart and the No. 1 on the Viral 50 México chart.

She performed on the NPR Music Tiny Desk series on 27 October 2017. In the first month of its presence on YouTube, it had been viewed more than 1,350,000 times. As of 25 August 2019 that same video had been viewed over 8,671,800 times.

In 2017, she recorded “Remember Me” as a duet with contemporary R&B singer Miguel for the credits of the movie Coco, and together they also performed the song at the 90th Academy Awards ceremony.