In the late 1990s, Valensi was part of an informal band with vocalist Casablancas and drummer Moretti in high school, and continued after he and Casablancas left Dwight. Nikolai Fraiture started playing as the bassist and the band was formed when guitarist Albert Hammond Jr. joined in fall 1998. Their first show as The Strokes was at the Spiral in New York City on September 14, 1999. The band released The Modern Age EP in 2001 under Rough Trade Records and was signed for a five-album record deal by RCA Records. The band released six LPs including Is This It, Room on Fire, First Impressions of Earth, Angles, Comedown Machine and The New Abnormal with tours and festival sets in the North America, Europe, South America, East Asia and Australia. Following the completion of their album contract deal with RCA Records in 2013, the band has continued to release new music through Casablancas’ Cult Records.

Valensi’s main guitar, which he uses for nearly every live show and recorded song, is a 1990s Epiphone Riviera with Gibson P-94 pick-ups, which was given to him by friend and fellow Strokes guitarist Albert Hammond Jr. In a 2004 interview with Epiphone, he called it “the greatest guitar never made” because Gibson had never produced a semi-hollow with humbucker-sized P-94 pickups. He has several models in different colours (all with P-94s), including multiple naturals, one in vintage sunburst, one in red, and a 12-string elite in red. In 2005, Epiphone released a signature model of his guitar, the Elitist Nick Valensi Riviera P-94, and followed it up with a standard model Nick Valensi Riviera P-94 in 2007. Back-up/warm-up guitars include an Epiphone Dot fitted with 2 P-94s, an Epiphone Casino, an Epiphone Sheraton, and a Gibson Faded Special Double Cutaway with 2 P-90s. Valensi often borrows fellow Strokes guitarist Albert Hammond, Jr.’s backup guitars, which include a Gibson Les Paul Jr. and a Les Paul Special. New guitars used for the First Impressions of Earth tour include a Les Paul Custom in black, a Fender Telecaster Custom (which he can be seen using in the music video for Under Cover of Darkness ), and a Duesenberg semi-hollow. Valensi’s main amplifier is a 2×12″ Fender Hot Rod DeVille, used with Fender 4×12″ extension cabinets during live shows. He also recently purchased a Carr amplifier to use on the last few stops of the First Impressions tour. His pedalboard consists of a Visual Sound Jekyll & Hyde Ultimate Overdrive pedal, Boss TR-2 Tremolo, Vox Cooltron Bulldog Distortion, MXR Micro Amp (2) and a Boss TU-2 Chromatic Tuner. He has also been seen with an Electro Harmonix Memory Man and a Boss Blues Driver.

While much of his career has been focused on playing and writing for The Strokes and CRX, Valensi has also contributed as a session musician and songwriter to some of his contemporaries. One of his first notable credits doing so was playing guitar for Regina Spektor’s song “Better,” which was released on her 2006 album Begin to Hope and also published as a single in a slightly different version on which the guitar parts are rearranged.

In the summer of 2006, Nick married his girlfriend of five years, English photographer and television personality Amanda de Cadenet. With De Cadenet, Valensi has fraternal twins, Silvan and Ella, born on October 19, 2006. He has a step-daughter, Atlanta, through De Cadenet’s first marriage. De Cadenet published a book of photographs entitled Rare Birds in 2005, which includes several pictures of Valensi, whom she refers to as her “muse” on her website. Valensi has lived with his family in Los Angeles since the mid-2000s. In the past, they have lived in the neighborhoods of Van Nuys and Studio City in Los Angeles and in Midtown Manhattan and Park Slope in New York City.

He has collaborated with artists Devendra Banhart, The Stroke’s Moretti, and Sia on multiple occasions. Nick Valensi sang backing vocals and played guitar for Devendra Banhart’s song “Shabop Shalom” on the 2007 album Smokey Rolls Down Thunder Canyon. Furthermore, he contributed backing vocals on the self-titled debut album of his bandmate Fab Moretti’s band, Little Joy. He appears in the video for “No One’s Better Sake” by Little Joy as drummer. He also appears in the video for “Adam & Steve,” a song by Devendra Banhart and Moretti’s side project Megapuss.

He plays guitar on Sia’s album 2010 We Are Born and has also written several hooks and melodies on it. Sia has also stated that she and Valensi are planning to write songs together for other artists. He also co-wrote the track “Hostage” on Sia’s 2014 album 1000 Forms of Fear. Other credits include co-writing with Brody Dalle in 2014, Kate Pierson for her 2015 album Guitars and Microphones, Kesha, and again with Sia for the 2017 Blondie track, “Best Day Ever.”

In 2013, Valensi co-founded the Los Angeles-based rock band CRX. He is the frontman of the group, and is backed by drummer Ralph Alexander, multi-instrumentalist Brad Oberhofer, bassist Jon Safley, and guitarist Darian Zahedi. The band released their debut album, New Skin, on October 28, 2016. This was followed by the 2019 record Peek. Valensi has described the band’s sound as a mix of power pop and heavy metal, and has named The Cars, Cheap Trick and Elvis Costello as influences.