In the 19th century, Port Clyde became a busy port featuring granite quarries, tide mills for sawing timber, and shipbuilding and fish canning businesses. By the 20th century, the area attracted artists and writers.The Country of the Pointed Firs was written by Sarah Orne Jewett in St. George.
Port Clyde's harbor was originally known as Herring Gut. Marshall Point – site of the Marshall Point Lighthouse– is Port Clyde's southernmost extremity. This lighthouse is the one to which Tom Hanks ran in the 1994 film Forrest Gump
The Wyeth family, with three generations of accomplished artists, has owned a summer home in Port Clyde ever since N.C. Wyeth purchased "Eight Bells" in the early 1920s. His son Andrew Wyeth long owned property and spent time in the area, as does N.C.'s grandson, Jamie Wyeth. Andrew's widow Betsy owns two islands off Port Clyde.
Supreme Court Chief Justice John Roberts and his wife purchased a home on Hupper Island just off the coast of Port Clyde in 2006. The house is a one-story structure built in the 1960s and reportedly purchased for $475,000. The seller of the home was "This Old House" star Steve Thomas, according to the Knox County Registry of Deeds. Mr. Thomas still owns an older renovated barn and house just across a trail from the Chief Justice's home.
Kenneth Noland, one of the best known American color field painters, spent the last several years of his life in Port Clyde. There he worked regularly at his studio and owned a home with his wife, Paige Rense, Editor-in-Chief of Architectural Digest.
Port Clyde is the site of Fieldstone Castle, built by Russell W. Porter, currently inhabited by artist Greg Mort as his summer studio.