Ex-hippy Ben Parker lived in a commune for a short time before he met his wife, May. A kind and good-natured man, Ben found married life agreeable and his family welcomed his wife as one of their own. Ben was close to his younger brother, Richard, and his family, often spending time with them and the family of Richard's partner, Eddie Brock; when Richard and his wife died in a plane crash, Ben and May took in their nephew, Peter. Uncle Ben took over as Peter's father figure, and as Peter grew older, Ben recognized his nephew's intelligence and did his best to encourage him in academics. Perhaps because of his intelligence, Peter was often bullied, and Ben did his best to prevent it, even going so far as to join Peter during a certain lunch hall and convincing Peter's old friend, Mary Jane Watson, to sit with them. During a field trip to Oscorp the next day, Peter was bit by the experimental "00" spider, causing him to faint and giving him amazing powers - powers Ben never suspected. CEO Norman Osborn, fearful the Parkers would sue, picked up the hospital bill, but Ben never considered a lawsuit, worrying it would break up Peter's friendship with Norman's son, Harry Osborn.

Several days later, the parents of Peter's classmate, Flash Thompson, called Ben and threatened to sue the Parkers because Peter had accidentally broken Flash's hand defending himself in a fight. Ben agreed to pay the hospital bill, even though he believed the altercation to be Flash's fault, as there was no way they could afford a lawyer. Their financial worries abated when they began receiving letters filled with cash, allegedly donated by Peter's teachers; in truth, the money was from their nephew, who was secretly earning it by wrestling.

As Peter took advantage of his newfound powers by joining the basketball team, his grades plummeted, causing a loud argument with Ben. Peter ran away from home, staying at classmate Kong Harlan's house. In his parent's absence, Kong threw a large party; arriving there, Ben pulled Peter outside for a heart-to-heart talk. Ben told Peter his father's philosophy on life, "if there are things you do better than anyone else, things you could do to help people, it is your responsibility to do them." Overcome with emotion, Peter ran away again.

Dejected, Ben went home where he discovered a burglar, ironically a man Peter had refused to stop during another robbery just hours before. The burglar demanded money, but Ben joked with him saying, "you probably have more money than we do." Angered, the burglar shot Ben, killing him.