Sanders was born in 1946 in Richlands, North Carolina. He attended James B. Dudley High School in Greensboro, North Carolina, where he played for the football, baseball, and basketball teams.
Sanders attended the University of Minnesota, where he played college football for the Minnesota Golden Gophers. He was named to the All-Big Ten Conference Team in his senior year, when he recorded 21 receptions for 276 yards with two touchdowns, as Minnesota tied for the Big Ten championship with an 8–2 record.
The Lions selected Sanders in the third round of the 1968 NFL Draft, and he became their starting tight end for the next 10 seasons. He had 336 career receptions for 4,817 yards and 31 touchdowns. He was also known as a superior blocker. He was chosen for the Pro Bowl seven times (1968–1971 and 1974–1976). He was the only rookie to be named to the 1969 Pro Bowl, following a season where he had 40 receptions for 533 yards. Sanders was also selected as a first-team All-Pro for the 1970 and 1971 seasons, receiving the most votes of any player in both years. During an exhibition game in 1976, Sanders injured his right knee, ending his career.
Sanders was named to the NFL 1970s All-Decade Team as selected by voters of the Pro Football Hall of Fame. Sanders was inducted into the North Carolina Sports Hall of Fame in 1997, and the Minnesota M Club Hall of Fame in 2013. In 2008, Sanders was chosen as a member of the Lions' 75th Anniversary All Time Team.
Sanders served as a color analyst on Lions radio broadcasts from 1983 through 1988, worked with the team as an assistant coach in charge of wide receivers from 1989 to 1996, returned to perform radio broadcasts in 1997, and then joined the Lions' front office as a scout. He became the team's assistant director of pro personnel in 2000, and held the role until his death. In 2005, he co-authored Charlie Sanders' Tales from the Detroit Lions, a book of anecdotes about the team and its players.
Sanders also worked in the team's community relations department and served as a spokesman for the United Way and The March of Dimes. He created The Charlie Sanders Foundation in 2007, which provided two college scholarships per year for students from Oakland County, Monroe, Michigan and his home state of North Carolina. In 2012, he began the "Have A Heart Save A Life" program (within the foundation) to raise funds to provide heart (EKG) screenings to young people. In August 2012, the first "Charlie Sanders Have A Heart Save A Life Celebrity Golf Outing was held in West Bloomfield, Michigan. St. Jude Children's Research Hospital honored Sanders for his charitable work in 2014.
Sanders and his wife, Georgianna, had nine children and lived in Rochester, Michigan. One of his daughters, Mary Jo is a pro boxer, and three of his sons played college football: one at Ohio State University, and had a brief NFL career with the Detroit Lions; one son formerly played at Saginaw Valley State University; and one son is currently playing at Saginaw Valley State University, after transferring from Michigan State University.
Sanders developed a malignant tumor behind his right knee, which was discovered while he was undergoing knee replacement surgery. Sanders underwent chemotherapy, but died on July 2, 2015 in Royal Oak, Michigan from cancer.