Samaire Armstrong was born in Tokyo, Japan to a Scottish father, Hunter Armstrong, and an Italian mother, Sylvia. Armstrong lived in Japan for several years, before moving to Hawaii and later Sedona, Arizona where she grew up and attended Sedona Red Rock High School. She has also lived in Malaysia and China. She attended the University of Arizona for a year to major in costume design and theatre. After her departure from school, she moved to Los Angeles.

Armstrong's first major break into film acting was as one half of the conjoined twins the Fratelli sisters in the parody movie Not Another Teen Movie and the teen movie "It's a Boy Girl Thing" co-starring with Kevin Zegersin which she plays a hopelessly geeky teenager girl. Armstrong also had a recurring role on Freaks and Geeks, and had guest appearances on Judging Amy, Party of Five, C.S.I.: Miami, Numb3rs and the The X-Files. Armstrong appeared in The O.C. for one episode, and was brought back at fan request for several episodes of the first season. She also had a recurring role on the HBO television series Entourage. Her most recent film projects include Stay Alive, Just My Luck, and Rise. Armstrong was also a part of the cast in the drama Dirty Sexy Money.

When not acting, Armstrong is often designing clothes for her own clothing brand, called NARU. Her line is currently only available in a few exclusive boutiques in Hawaii, but Armstrong is hoping to get stores also across the United States.

She has also appeared in music videos, including Hanson's "Penny and Me" and Daniel Powter's "Bad Day".