Nelson was working as a waiter at T.G.I.Friday's and doing occasional stand-up comedy when he was offered a job on Mystery Science Theater 3000, typing the suggestions in the writing room. The writers told him to feel free to make some comments on the movies they were watching, and Nelson impressed them so much with his wit and comedic timing that they made him a staff writer, and, later, head writer. When series originator and host Joel Hodgson decided to leave the show half-way through the fifth season, he chose Nelson as his replacement, reportedly because he thought Nelson was a natural leader, a gifted comedian and a gifted muse, and also because Nelson simply looked good standing next to the show's puppets.
Since the series ended, Nelson has worked steadily as a writer, publishing several books: Mike Nelson's Movie Megacheese, Mike Nelson's Mind Over Matters and Mike Nelson's Death Rat!, the last being his first novel. He also wrote for the short-lived game show Let's Bowl, which gained a cult following of its own.
In 2006, Nelson was appointed Chief Content Producer for Legend Films. He is responsible for building and leading the company's creative content, providing continuous commentaries, and developing other premium web-based programming. "I'm very excited. Legend Films is such a great fit for me—talented people who consistently put out a great product. Plus, there are Flaming Hot Cheetos in the lunch room vending machine. That made it an easy choice to join the team."
One of the projects put together by Nelson and Legend Films was RiffTrax, a website offering the purchase of downloadable audio commentaries once again costarring two former MST3K cast members Kevin Murphy and Bill Corbett. The first commentary made available through the service was for Road House.
Nelson has been married to fellow MST3K writer Bridget Nelson since 1990.
In 2014, RiffTrax published Mike Nelson's list of favorite riffs. They included:
- Willy Wonka and the Chocolate Factory
- The Karate Kid, Part III
- The Incredible Hulk: The Final Round
- Little Lost Scent (Short)
- Setting Up A Room (Short)
- Unto the Least of These (Short)