As the audience for comic books began gravitating towards young boys in the mid-to-late 1950s, the Superman stories shifted in focus more toward science fiction-inspired plots involving extraterrestrials, fantasy creatures and bizarre, often contrived, plots. Lois Lane's main interests in various late 1950s and 1960s stories became vying with her rival Lana Lang for Superman's affections, attempting to prove Clark Kent and Superman were one and the same, and tricking or otherwise forcing Superman into marriage. For Superman's part, his rationale for resisting her is that she cannot be trusted not to expose his secret identity to advance her career and marrying her would put her in too much danger from his enemies (ignoring the fact that his romantic relationship with her, thus her value as a hostage, is already public knowledge). This change in Lois' personality from her earlier 1940s self might also be a result of American society's attitudes toward women and their societal roles in the 1950s. Across this generation, she got married quite frequently, to other well known characters such as Batman and Jimmy Olsen and on one occasion a convicted criminal on death row (and various Superman pastiches) but these marriages were always annulled or otherwise forgotten.

Lois became more and more popular during this decade, and after appearing as the lead character in two issues of DC's title Showcase in 1957, Lois was given her own comic, titled Superman's Girl Friend, Lois Lane beginning in March 1958. Most of the stories in this title placed a greater emphasis on Lois' romance with Superman, and were drawn by artist Kurt Schaffenberger; indeed, Schaffenberger's rendition of Lois became cited by many as the "definitive" version of Lois, and he was often asked to redraw Superman comic artist Curt Swan's renditions of Lois and Lana by Superman comic editor Mort Weisinger.

By the end of the 1960s, as attitudes toward women's role in American society began to change, Lois did as well. 1970s stories featuring Lois depicted her as being fully capable of taking care of herself, engaged in more solo adventures without Superman being involved, and her being much less interested in things such as discovering Superman's secret identity. For example, in her solo stories in Superman Family (an anthology title started in the mid-1970s from the merging/cancellation of several previous titles, including Superman's Girl Friend, Lois Lane and Superman's Pal, Jimmy Olsen), Lois regularly battled criminals in her investigations and defeated them with quick wits and considerable skill in the Kryptonian martial art of Klurkor, taught to her in the bottle-city of Kandor.

After the 1985-1986 miniseries Crisis on Infinite Earths, writer and artist John Byrne was hired to revise the Superman comics, thus eliminating the Silver Age version of Lois from continuity; before this happened, a final non-canonical "imaginary story" Whatever Happened to the Man of Tomorrow? was written by writer Alan Moore, meant as a send-off for the "pre-Crisis" versions of the characters, including Lois.