Huff was born and grew up in the No. 9 coal mining camp in Edna, West Virginia, The fourth child of six for Oral and Catherine Huff, he lived with his family in a small rowhouse with no running water. Huff grew up during the Great Depression, while his father and two of his brothers worked in the coal mines loading buggies for Consolidated Mining.
Huff attended and played high school football at the now-closed Farmington High School, where he was both an offensive and defensive lineman. While he was there, Huff helped lead the team to an undefeated season in 1951. He earned All-State honors in 1952 and was named to the first-team All-Mason Dixon Conference.
Then, defensive coordinatorTom Landry came up with the new 4–3 defensive scheme that he thought would fit Huff perfectly. The Giants switched him from the line to middle linebacker behind Ray Beck. Huff liked the position because he could keep his head up and use his superb peripheral vision to see the whole field. On October 7, 1956 in a game against the Chicago Cardinals, Beck was injured and Huff was put into his first professional game. He then helped the Giants win five consecutive games and they finished with an 8–3–1 record, which gave them the Eastern Conference title. New York went on to win the 1956 NFL Championship Game and Huff became the first rookie middle linebacker to start an NFL championship game.
"Landry built the 4-3 defense around me. It revolutionized defense and opened the door for all the variations of zones and man-to-man coverage, which are used in conjunction with it today."
In 1959, Huff and the Giants again went to the NFL Championship Game, which ended in a 31–16 loss to the Colts. Also that year, Huff became the first NFL player to be featured on the cover of Time magazine on November 30, 1959. He almost passed up the magazine appearance, demanding money to be interviewed, but relented when Time agreed to give him the cover portrait. Huff was also the subject of an October 31, 1960 CBS television special, "The Violent World of Sam Huff", broadcast as an episode of the Walter Cronkite-hosted anthology series The Twentieth Century. The network wired Huff for sound in practice and in an exhibition game.
"As long as I live, I will never forgive Allie Sherman for trading me."
Huff joined the Redskins in 1964 and they agreed to pay him $30,000 in salary and $5,000 for scouting, compared to the $19,000 he would have made another year with New York. The impact Huff had was almost immediate and the Redskins' defense was ranked second in the NFL in 1965.
On November 27, 1966, Huff and the Redskins beat his former Giant teammates 72–41, in the highest-scoring game in league history. After an ankle injury in 1967 ended his streak of 150 straight games played Huff retired in 1968.
Vince Lombardi talked Huff out of retirement in 1969 when he was named Washington's head coach. The Redskins went 7-5-2 and had their best season since 1955 (which kept Lombardi's record of never having coached a losing NFL team intact). Huff then retired for good after 14 seasons and 30 career interceptions. He spent one season coaching the Redskins' linebackers in 1970.
After leaving the NFL, Huff took a position with J.P. Stevens in New York as a textiles sales representative. He later joined the Marriott Corporation as a salesman in 1971, rising to vice president of sports marketing before retiring in 1998. While with Marriott, Huff was responsible for selling over 600,000 room nights via a partnership between the NFL and Marriott that booked teams into Marriott branded hotels for away games.
After retiring from football, Huff spent three seasons as a color commentator for the Giants radio team and then moved on in the same capacity for the Redskins Radio Network, where he remained until his retirement at the end of the 2012 season, calling games alongside former Redskins teammate Sonny Jurgensen and play-by-play announcers Frank Herzog (1979 to 2004) and Larry Michael (2005 to 2012). He was also a broadcaster for a regionally syndicated TV package of Mountaineer football games in the mid-1980s.
In 1982, Huff became the second WVU player to be inducted into both the College and Pro football Halls of Fame. In 1988, he was inducted into the WVU School of Physical Education Hall of Fame and, in 1991 he was inducted into the WVU Sports Hall of Fame.
In 1999, Huff was inducted into the National High School Hall of Fame and was ranked number 76 on The Sporting News' list of the 100 Greatest Football Players.