- John Howard Appleton, chemist
- Louisa Dow Benton, linguist and letter writer
- Hannah Johnson Carter, art educator
- Elisabeth Cavazza (1849–1926), author, journalist, and music critic
- Jennie Maria Drinkwater Conklin (1841–1900), author
- Leo Connellan, Beat poet and Poet Laureate of Connecticut
- Owen Davis, dramatist
- Robert F. Griffin, essayist
- Dorothy M. Healy, professor at Westbrook College and Curator of the Maine Women Writers Collection
- Stephen King, author
- Henry Wadsworth Longfellow, poet
- John Neal, author and critic
- Alan Taylor, historian
- William Irwin Thompson, poet and cultural historian
- Dorothy Appleby, American film actress
- Maria a'Becket, painter
- Hiram Abrams, motion picture mogul
- Bebe Buell, model, musician, and mother of Liv Tyler[citation needed]
- Howie Carr, radio personality
- Cody Christian, actor and rapper
- John Greenleaf Cloudman, artist, portrait painter and cabinet maker
- Charles Codman, painter
- Jerry Crasnick, sports journalist
- Kevin Eastman, co-creator of Teenage Mutant Ninja Turtles[citation needed].
- Greg Finley II, actor
- Frank Fixaris, sportscaster
- Francis Ford, actor
- John Ford, director
- Charles L. Fox, painter, labor unionist, and two-time candidate for Governor of Maine with the Socialist Party
- Adam Gardner, musician
- Peter Garland, composer
- Jeremiah Hacker, journalist and reformer
- Will Holt, songwriter
- Avery Yale Kamila, journalist and community organizer
- Anna Kendrick, actress
- Charles F. Kimball, artist
- Jennie Kimball, actor, soubrette, theatrical manager
- Linda Lavin, actress
- Tawny Little, television newscaster and Miss America (1976)
- Bob Ludwig, Grammy Award-winning audio mastering engineer
- Bob Marley, comedian
- Andrea Martin, actress
- Judd Nelson, actor
- Lincoln Peirce, comic strip creator, Big Nate
- Ryan Peters, aka Spose, rapper
- Victoria Rowell, actress
- Ethelynde Smith, concert singer and botanical painter
- Stuart Saunders Smith, composer and percussionist
- Brett Somers, actress
- Franklin Stanwood, painter
- Phyllis Thaxter, actress
- Liv Tyler, actress
- Louise Brown Verrill, composer
- James Alden Jr., rear admiral in the United States Navy
- George G. Gatley, brigadier general who commanded brigades and divisions in World War I[1]
- John H. Hall, inventor of the first United States Army breech-loading rifle
- Horatio Collins King, Medal of Honor recipient
- Charles J. Loring Jr., Medal of Honor recipient
- Holman S. Melcher, mayor, Civil War veteran
- Edward Preble, naval officer
- Herbert E. Schonland, Medal of Honor recipient
- Ronald Speirs, army officer with the Easy Company, 506 Parachute Infantry Regiment
- Peleg Wadsworth, Revolutionary War general
- Joseph Adams, state legislator
- Justin Alfond, President of the Maine Senate
- George H. Allan, state legislator and women's suffrage proponent
- Daniel W. Ames, Civil War veteran and state legislator
- James Appleton, state legislator and activist
- Joseph E. Brennan, 70th Governor of Maine
- Michael F. Brennan, Mayor and state legislator
- Joshua Chamberlain, Civil War veteran, governor, served as Surveyor of the Portland Port
- W. Edward Crockett, state legislator
- Winfred Thaxter Denison, United States Assistant Attorney General and Secretary of the Interior for the Philippines; born in Portland
- Santo DiPietro, Maine state legislator and businessman; born in Portland
- Neal Dow, mayor of Portland; Civil War general; temperance movement leader
- John Eder, state legislator and Maine Green Independent Party organizer
- William P. Fessenden, U.S. Senator
- Fletcher Hale, U.S. Congressman from New Hampshire
- Charles Harlow, mayor of Portland; state legislator
- Anne Haskell, state legislator
- Jon Hinck, state legislator and attorney
- John Lynch, U.S. Congressman
- George Mitchell, U.S. Senate Majority Leader (1989 to 1995); chairman of Walt Disney; U.S. special envoy to the Middle East
- Merle Nelson, state legislator
- William Pitt Preble, Justice of the Maine Supreme Court; U.S. Minister to the Netherlands; President of the St. Lawrence and Atlantic Railroad
- Anne Rand, state legislator
- Thomas Brackett Reed, U.S. Congressman; Speaker of the U.S. House of Representatives
- George Ruby, Black Republican legislator in Reconstruction-era Texas; raised in Portland
- James E. Thorne, state legislator[2]
- Charles W. Walton, U.S. Congressman
- Herman W. Waterman, politician from Wisconsin
- Edville Gerhardt Abbott, surgeon
- Oscar Cox, lawyer
- Walter M. Fleming, physician, founder of the Shriners
- Alexander Wadsworth Longfellow Jr., architect
- Robert E. McAfee, physician
- Alexander Parris, architect
- Lois Rice, College Board executive & education scholar
- Thomas J. Sparrow, architect
- Henry Aiken Worcester, 19th century minister & vegetarian
- Mike Brown (born 1975), mixed martial arts fighter
- Nik Caner-Medley (born 1983), basketball forward
- Dick Capp (born 1942), American football tight end and linebacker
- Ian Crocker (born 1982), Olympic swimmer
- Rob Elowitch (born 1943), wrestler
- Terry Farnsworth (born 1942), Canadian Olympic judoka
- Ryan Flaherty (born 1986), baseball second baseman
- Charlie Furbush (born 1986), baseball pitcher
- Rip Jordan (1889–1960), baseball pitcher
- Pete Ladd (born 1956), baseball pitcher
- Gary McAdam (born 1955), ice hockey forward
- Quinton Porter (born 1982), American football quarterback
- Joan Benoit Samuelson (born 1957), marathon runner
- Bob Stanley (born 1954), baseball pitcher
- Coley Welch (1919–2000), middleweight boxer
- Cornelia Dow (1842–1905), philanthropist, temperance activist; born and died in Portland, Maine
- Sarah E. Fuller (1838-1913), national president, Woman's Relief Corps; born in Portland, Maine
- Nathaniel Gordon, only American slave trader to be tried, convicted, and executed under the Piracy Law of 1820 "for being engaged in the Slave Trade"
- L. Isabel Heald (1842–1932), social leader and philanthropic worker
- Ellen Martin Henrotin, social reformer; born in Portland, Maine
- Augusta Merrill Hunt (1842-1932), philanthropist, suffragist, temperance leader; lived in Portland her entire life
- Lois Galgay Reckitt (born 1944), executive director of Family Crisis Services, Portland, Maine
- Frederick L. Small (1866–1918), stockbroker; convicted and hanged by the state of New Hampshire for the murder of his wife