In 1977, Mary Jane was engaged to Harry Osborn. Whilst she was at a disco, she began arguing with Peter Parker about how he was a coward and never dealt with anything head on. During the argument, she revealed to him that she knew that he was Spider-Man since she was fifteen years old. A year after Gwen Stacy was killed, Mary Jane helped see off the clones of Gwen and Peter (now called Ben and Helen Parker). Afterwards, she went into Peter's apartment to see how he was doing, but he instead complained about how the clones now had new lives and she also had the life she wanted without even having to sleep with Harry now that he disappeared. Believing he now had nothing, Mary Jane comforted him and told him that wasn't true at all.
By 1984, Mary Jane and Peter fell in love and got married. While Peter was fighting alongside other heroes on Battleworld, Mary Jane was in hospital with a senile Aunt May, about to give birth to twins at any moment. After Peter finally returned from Battleworld with a new black suit, Mary Jane finally introduce him to their children, Claire and Benjamin Parker. After May wondered off while Peter was gone, Mary Jane considered having May being put in a senior's home, which Peter was strongly against. When Peter was seemingly killed by Kraven the Hunter, the sentient black suit broke out of containment to look for Spider-Man. Mary-Jane followed it, only to find it re-bonded to Spider-Man, who was just about to kill Kraven. On Peter's word, Mary Jane used a fail-safe made by Peter to be used against him if the Symbiote ever got out of control. The fail-safe was a success, but the experience made Mary Jane decide to leave Peter along with the twins, to ensure her family's safety.
Peter and Mary Jane seemingly reconciled when Peter stepped away from Spider-Man and left Parker Industries in the hands of his clone, Ben. The Parkers lived in anonymity for over a decade, but when Ben was killed by the vampiric Morlun in 2006, thus indirectly revealing Peter's identity to the world, Peter traveled to New York to reveal himself to the public. He did this as a means to lure Morlun away from Mary Jane and their children, but instead Morlun directly attacked the Parker household. Mary Jane attempted to flee into the wilderness with her children, but when Benjy put together than Morlun was susceptible to injury when feeding, he sacrificed himself for Claire to impale him.
In 2019, after Doctor Doom had put the world under his regime, Mary Jane along with Ben and Claire, accompanied Peter and Miles Morales, with Doc Ock's mind, into the Quinjet in order for them to activate a device left by Tony Stark which would deactivate Doom's technology and set the world free. However, this would be Peter's last journey as he died while helping Otto escape. After, Miles got back to his old body, Mary Jane gave Miles Peter's original costume for him to continue the legacy.