Jamie Wyeth was born and raised in Chadds Ford, Pennsylvania. Being the grandson of N. C. Wyeth and the son of Andrew Wyeth, he is a third-generation artist. Jamie also had two aunts, Carolyn Wyeth and Henriette (Wyeth) Hurd, as well as two uncles, Peter Hurd and John McCoy, who were all painters. In addition to these family members, Jamie Wyeth also had a mother named Betsey and an older brother named Nicholas.

Jamie Wyeth began painting at a young age. He would often express his artistic abilities by imitating a movie he had seen, or a book he had read. Having attended public school until grade six, his father decided that an official education was no longer necessary for an artist. Therefore, Jamie began to attend English and History lessons in the morning and would spend the rest of the day working in his Aunt Carolyn's studio. He spent his first year drawing spheres and cubes. Although this tended to bore Jamie, he still recognized the importance of these two basic artistic fundamentals. Rather than teaching Jamie, his father instead allowed Jamie to do his own work and only offered him beneficial criticism. Unlike any ordinary student, instead of spending time playing sports, games, or participating in any social activities, Jamie spent eight hours each day sketching, painting, and studying art.

By the age of 18, Wyeth's paintings could be found in the Wilmington Society of Art in Wilmington, Delaware and in the William A. Farnsworth Library and Art Museum in Rockland, Maine, in addition to several other locations. Wyeth began to incorporate oil in his paintings of portraits. He studied anatomy for a year in New York by working Saturdays at a hospital morgue in Harlem. In his portraits, he incorporated both the physical appearance and the personality of his subjects. Although he was widely known by name due to his infamous family, Wyeth had to experience disapproval by critics of New York who thought his paintings did not fit well with the New York artistic attitude. Several critics considered Andrew Wyeth's paintings to be too standard and Jamie's paintings to be too realistic.

Wyeth served in the Delaware Air National Guard from 1966-1971. During this time, he painted a portrait of Charles L. Terry, the governor of Delaware. This was a rare occasion in which he accepted money for his artwork. Another major portrait the young Wyeth did was of President John F. Kennedy. In order to acquaint himself with the president, Wyeth studied photos and footage, and spoke to several people who were very close to Kennedy, such as the president's widow. In addition, Wyeth sketched the two brothers of John F. Kennedy, Robert and Edward.

Wyeth joined the Eyewitness to Space program, sponsored by both NASA and the National Gallery of Art in Washington. Wyeth covered launchings and splashdowns in this program for recording details of United States space probes. Wyeth made trips from Washington to Maine during the year of 1974 to paint pictures of Watergate. He sketched situations of the Senate and Supreme Court that related to Watergate, as well as important courtroom settings.

Currently, Jamie Wyeth lives with his wife Phyllis in both Mohegan, Maine and Chadds Ford, Pennsylvania. He continues to be fascinated by animals, people, and wildlife. The isolation portrayed in his Maine paintings allowed for his paintings to be the central plot of the ABC-TV series Kingdom Hospital, produced by Stephen King. He is represented by the Warren Adelson Gallery.