Louise modeled for artist Bernie Wrightson's cover of DC Comics' House of Secrets #92 (June–July 1971),[4][5] the first appearance of Swamp Thing,[6] and was hired by McFadden-Bartell, a magazine publisher and distributor and worked there for three years.

[3] Louise met the comic book writer and artist Walt Simonson in 1973, began dating in August 1974,[7] and married in 1980.

[9] In January 1980, Jones joined Marvel Comics, where she initially worked again as an editor, most notably on Uncanny X-Men, which she edited for almost four years (#137–182) and Conan the Barbarian (#114–148 ).

[15] Instead, Layton ended up dropping X-Factor shortly after, and at Chris Claremont and Ann Nocenti's suggestion, Harras chose Simonson as his replacement.

In #25, the creators gave the character, Angel, blue skin and metal wings in a process which led to his being renamed as "Archangel".

It was at Simonson's suggestion that X-Men writer Chris Claremont's "Mutant Massacre" story idea was turned into a crossover through all the "X-books", the first of its kind.

[19] In 1988–89, she and her husband co-wrote the Havok and Wolverine: Meltdown limited series painted by Jon J Muth and Kent Williams.

Simonson was one of the many creators who worked on the Superman: The Wedding Album one-shot in 1996 wherein the title character married Lois Lane.

The next year, she scripted the five-part limited series X-Factor Forever and reunited with June Brigman for a new Power Pack story in Girl Comics #3.

Simonson wrote the "Five Minutes" chapter in Action Comics #1000 (June 2018)[26] and a twelve-part webcomic tie-in to The Death of Superman animated movie.

[29][30] In April 2022, Simonson and her husband were reported among the more than three dozen comics creators who contributed to Operation USA's benefit anthology book, Comics for Ukraine: Sunflower Seeds, a project spearheaded by IDW Publishing Special Projects Editor Scott Dunbier, whose profits would be donated to relief efforts for Ukrainian refugees resulting from the February 2022 Russian invasion of Ukraine.

[31][32] Simonson teamed up with artist June Brigman to produce an original story with new characters created specifically for the anthology.

In 2024, the five-issue retro series Power Pack: Into the Storm by Simonson and June Brigman, with a story that takes place during their original run, was published by Marvel.