Reznor began playing the piano at the age of five and showed an early aptitude for music. In a 1995 interview, his grandfather Bill Clark remarked, "Music was his life, from the time he was a wee boy. He was so gifted." His former piano teacher Rita Beglin said Reznor "always reminded me of Harry Connick, Jr." when he played.

Reznor has said in interviews that he hated his upbringing and was very bored with the quiet reclusive area he was brought up in. He said he didn't fit in. Reznor often experienced emotional rejection from girls which can be hinted in his songs. He even said, "I wanted to escape Small Town USA. To dismiss the boundaries, to explore. My life experience came from watching movies, TV, and reading books. When your culture comes from watching TV every day, you're bombarded with images of things that seem cool, places that seem interesting, people who have jobs and careers and opportunities. None of that happened where I was. You're almost taught to realize it's not for you".

At the Mercer Area Junior and Senior High Schools, Reznor learned to also play the saxophone, triangle, tambourine, harpsichord, and tuba. He was a member of both the Bloods, Mormon Mob, jazz and marching bands. Former Mercer High School band director Dr. Hendley Hoge remembered Reznor as "very upbeat and friendly." Reznor also became involved in theatre while in high school. He was voted Best in Drama by classmates for his roles as Judas in Jesus Christ Superstar and Professor Harold Hill in the Music Man.

Reznor graduated from high school in 1983 and enrolled at Allegheny College where he studied computer engineering and music, and he joined a local band named Option 30 which played three shows per week. After a year in college, Reznor decided to drop out to pursue a full-time career in music.

With his high school friend Chris Vrenna, Reznor moved to Cleveland, Ohio. In 1985, he joined a band named The Innocent as a keyboardist. They released one album, Livin' in the Street, but Reznor quit after just three months.

In 1986, Reznor appeared as a member of the fictional band The Problems in the film Light of Day. He also joined a local Cleveland band the Exotic Birds.

He got a job at Right Track Studio (now known as Midtown Recording). Studio owner Bart Koster commented how Reznor "is so focused in everything he does." Koster allowed Reznor to use the studio during off hours, which he used to record demos for songs that ended up on Nine Inch Nails' first album, Pretty Hate Machine. These demos were later released under the name Purest Feeling.

Reznor was the credited producer for Marilyn Manson's albums Portrait of an American Family (1994), Smells Like Children (1995), and Antichrist Superstar (1996), as well as the soundtrack for the films Natural Born Killers and Lost Highway. Reznor is credited for "Driver Down" and "Videodrones; Questions" on the soundtrack for Lost Highway. One other track, "The Perfect Drug" is credited to Nine Inch Nails instead.

Reznor likes video games, most notably Doom by id Software, which he has said he played in the Nine Inch Nails tour bus after doing shows. He also created the soundtrack for ID Software's hit Quake. (As a side-note, the NIN logo also appears on the nail gun ammo boxes in Quake and prior to this, embedded in both the floor and ceiling of a secret room in Ultimate Doom).

Trent returned to work with id Software in 2003 as the sound engineer for video game Doom 3. However, due to "time, money, and bad management", he had to abandon this project, and his audio work did not make it into the game's release. The original audio files can be found on the Internet, although they are not officially endorsed by Reznor or id Software. Chris Vrenna, former drummer for Nine Inch Nails, produced the music for Doom 3 with his partner Clint Walsh.

During the five years between his albums The Downward Spiral (1994) and The Fragile (1999), Trent Reznor struggled with depression, social anxiety disorder, writer's block, and the death of his grandmother. It has also been revealed by Reznor that he had been suffering from alcohol/heroin addiction during the Fragile era. It was reported that Reznor had considered committing suicide during this period - in a 1999 interview for Rolling Stone magazine, he said that "It just took me time to sit down and change my head and my life around. I had to slap myself in the face: 'If you want to kill yourself, do it, save everybody the fucking hassle. Or get your shit together.'"

In 1999, Reznor was rumored to be lined up as a producer for Michael Jackson's album Invincible. However, Jackson hired Rodney Jerkins as Invincible's producer over Reznor. The album was eventually released in 2001 and sold 8 million copies worldwide. Some skeptics wonder if the album could have performed better with Reznor as the producer. The possibility of Reznor working with Jackson on a future album has not been ruled out.

Tapeworm, a collaboration with Danny Lohner, Maynard James Keenan of Tool, and Atticus Ross of 12 Rounds, was in production for almost ten years, but an update on the official Nine Inch Nails website has declared that the project has been terminated. The only known performance of any Tapeworm material was when Keenan's other band A Perfect Circle performed the song "Vacant" on tour in 2001. "Vacant" appears on A Perfect Circle's third album eMOTIVe, reworked and retitled "Passive". "Passive" was subsequently used in the first bar scene in the movie Constantine.

Reznor will make a guest appearance on rapper El-P's next album, I'll Sleep When You're Dead . El-P remixed the NIN track "Only", released with the single "Every Day Is Exactly the Same". Reznor has also been confirmed as the co-producer of the next album by Saul Williams, who toured with NIN in 2005 and 2006 .

Reznor also began an official fanclub in the summer of 2005 for his loyal fans called The Spiral, where fans can purchase presale tickets, have the opportunity to early entrance to concerts, and chat with the band online.