Following Steve Ditko's departure after issue #38 (in July 1966), John Romita Sr. replaced him as penciler and would draw the series for the next several years. An early 1970s Spider-Man story led to the revision of the Comics Code. Previously, the Comics Code forbade the depiction of the use of illegal drugs, even negatively. However in 1970, the Richard Nixon administration's Department of Health, Education and Welfare asked Stan Lee to publish an anti-drug message in one of Marvel Comics' top-selling titles. Amazing Spider-Man #96–98 (in May - July 1971) feature a story arc depicting the negative effects of drug use. In the story, Peter Parker's friend, Harry Osborn, becomes addicted to pills. When Spider-Man fights the Green Goblin (Norman Osborn), Spider-Man defeats the Green Goblin, by revealing Harry Osborn's drug addiction. While the story had a clear anti-drug message, the Comics Code Authority refused to issue its seal of approval. Marvel Comics nevertheless published the 3 issues without the Comics Code Authority's approval or seal. The issues sold so well that the industry's self-censorship was undercut and the Comics Code was subsequently revised.

Despite his super powers, Parker Parker struggles to help his widowed aunt pay rent, is taunted by his peers - particularly football star Flash Thompson - and, as Spider-Man, engenders the editorial wrath of newspaper publisher J. Jonah Jameson. As he battles his enemies, Peter Parker finds juggling his personal life and costumed adventures difficult. In time, Peter Parker graduates from high school, and enrolls at Empire State University (a fictional institution evoking the real-life Columbia University and New York University), where he meets roommate and best friend Harry Osborn and first girlfriend Gwen Stacy, and Aunt May introduces him to Mary-Jane Watson. As Peter Peter deals with Harry Osborn's drug problems, and Harry Osborn's father is revealed to be Spider-Man's nemesis, the Green Goblin, Peter Parker even attempts to give up his costumed identity for a while. Gwen Stacy's father, New York City Police detective Captain George Stacy is accidentally killed during a battle between Spider-Man and Doctor Octopus (in Amazing Spider-Man #90, published in November 1970). In the course of his adventures, Spider-Man has made a wide variety of friends and contacts within the super-hero community, who often come to his aid when he faces problems that he cannot solve on his own.

In Amazing Spider-Man #121 (in June 1973), the Green Goblin throws Gwen Stacy from a tower of either the Brooklyn Bridge (as depicted in the art) or the George Washington Bridge (as given in the text). She dies during Spider-Man's rescue attempt ; a note on the letters page of issue #125 states : « It saddens us to say that the whiplash effect she underwent when Spider-Man's webbing stopped her so suddenly was, in fact, what killed her. ». In the following issue, the Green Goblin appears to accidentally kill himself in the ensuing battle with Spider-Man.