Originally written by Sean McKeever with art by penciller Takeshi Miyazawa (who left after issue #15 and was replaced by David Hahn, but continued providing covers) and colorist Christina Strain, the series began publication in December 2005 and was preceded by two miniseries from the series' original creative team, Mary Jane in 2004 and Mary Jane: Homecoming in 2005.

The original series ended in July 2007 with issue #20 and was followed by a five-issue miniseries, Spider-Man Loves Mary Jane Season 2, in August 2008 by writer Terry Moore and artist Craig Rousseau.

Marvel had decided to launch a comic book series with a female lead to attract young female readers after seeing a growing number of girls becoming comic readers through manga, and had chosen Mary Jane Watson because of her popularity stemming from the Spider-Man film series (Spider-Man 2 was released two weeks after Mary Jane #1).

Simultaneously, a collected edition of the series was also released in magazine size with a cardstock cover, exclusively available at Target Stores.

After the initial sales figures for the digest came in, Marvel announced a second four-issue miniseries, Mary Jane: Homecoming, which began publication in March 2005.

[4] Beginning with May 2006's Spider-Man Loves Mary Jane #6, guest artist Valentine De Landro took over from Miyazawa for two issues, illustrating the so-called "Dark MJ Saga" (the title being a reference to the "Dark Phoenix Saga", a popular X-Men storyline), which retells Spider-Man's origin from Mary Jane's point of view.

For example, Mary Jane lives with her parents, not with her Aunt as she did in the original continuity, and she has a crush on Spider-Man (although she develops stronger feelings for Peter Parker).

Mary Jane decides to get a job to be able to afford her dress for the Homecoming dance, and because she feels dependent on Harry as he is paying for everything on their dates.

After the game, Mary Jane waits for Flash at his home and returns his notebook, telling him that she is not going to do anything about his crush on her and that, contrary to what he might assume due to her constant insults, Liz really loves him.

Flash, who still is not over his crush on Mary Jane, thinks fate brought them together and tries to kiss her during the ceremonial post-crowning dance, just as Liz comes back.

Mary Jane wins the lead in the school's production of Twelfth Night, angering another actress, Lindsay Leighton.

They have a pleasant but unsatisfying date, and Mary Jane finally realizes that Spider-Man’s job as a superhero (as well as his hidden identity) would make a romantic relationship impossible.

Trying to hide her pain, Mary Jane develops the public persona of an unflappable, flirtatious party girl.

Gwen's relationship with Peter comes under stress due to several of his unexplained absences and weak excuses during their dates (in actuality, he leaves abruptly to fight crime as Spider-Man).

Spider-Man soon acquires a new love interest, the redheaded mutant superhero Firestar, but is apprehensive about sharing his private life with her.

As Peter Parker, Spidey faces the hopeless task of maintaining a friendship with Gwen despite her wanting him as a boyfriend, and refusing anything else.

She lands a lead role in the play, beating out a girl named Zoe McCall, someone she was on friendly terms with before casting was finalized.

After Mary Jane lands a role in the play, someone starts a smear campaign on the school computers, calling her a "diva dork of Midtown High".

She is further proven wrong when he tells her the IP address is linked directly to the school and in an area prohibited to students.

Despite the suspect legality of the website, Mary Jane doesn't hold a grudge against Zoe and promises to keep the incident between the two of them.

The individual comic books are being collected into digest-sized trade paperbacks as part of Marvel's line of digests, with each volume reprinting five issues of the monthly series (four for the two initial miniseries).