He played high school football at Abraham Clark High School in Roselle, New Jersey, graduating in 1951.

After playing on the defensive line on the Penn State University football team, Grier was drafted as the 31st overall pick in the third round of the 1955 NFL Draft by the New York Giants. He played with the Giants from 1955 to 1962, during which he led the team to a NFL Championship in 1956 and the Eastern Conference Championship in 1958, 1959, 1961 and 1962. Grier was selected for the Pro Bowl in 1956 and 1960, and was named All-Pro at the defensive tackle position in 1956 and 1958–1962.

Grier was then traded in July 1963 to the Los Angeles Rams in exchange for defensive tackle John LoVetere and a high future draft pick. He was part of the “Fearsome Foursome”, along with Deacon Jones, Merlin Olsen, and Lamar Lundy, considered one of the best defensive lines in football history. His career ended in 1967 due to a torn Achilles tendon. Despite being the oldest member of the Fearsome Foursome, Grier is the last surviving member following the death of Deacon Jones on June 3, 2013.

Grier served as a bodyguard for his friend, United States senator and presidential candidate Robert F. Kennedy. He was guarding Ethel Kennedy, the Senator’s wife, who was then expecting a child, the night that Kennedy was assassinated in Los Angeles in 1968. Grier and Olympic decathlon gold medalist Rafer Johnson heard shots fired ahead of them. As Grier caught up he saw men wrestling with gunman Sirhan Sirhan. Grier jumped into the fray. Grier states, “So I see George Plimpton has the gun pointed at his face, and I’m concerned that it is going to go off, so I put my hand under the trigger housing and I pulled back the hammer so it couldn’t strike. I wrench the gun from Sirhan. I find the pin and I ripped it out and held it. Now I have the gun in my hand, so I shove it in my pocket.” Grier later said, “I grabbed the man’s legs and dragged him onto a table. There was a guy angrily twisting the killer’s legs and other angry faces coming towards him, as though they were going to tear him to pieces. I fought them off. I would not allow more violence.”

In December 1968, he accompanied Bob Hope on “Operation Holly,” Hope’s 1968 USO tour, Grier performed alongside headliner Ann-Margret and others at the U.S. bases at Long Bình, Cam Ranh Bay, Da Nang, Chu Lai, and Phù Cát, as well as aboard the carrier USS Hancock and the battleship USS New Jersey, and at Korat Royal Thai Air Force Base and U-Tapao Royal Thai Navy Airfield in Thailand, along with stops in South Korea and Guam.

Grier has appeared in a number of films and television shows. One of the first football stars to successfully make the transition to acting, he made about 70 television guest appearances. They include a role as one of the security contingent in “The Brain Killer Affair” episode of The Man from U.N.C.L.E. (1964), as well as a cameo playing an athletic trainer in an episode of I Dream of Jeannie. He became a regular cast member, starting in 1969, on the series Daniel Boone, Make Room for Granddaddy, and The White Shadow. In one White Shadow appearance, he donned his No. 76 Los Angeles Rams jersey from his NFL playing days.

Grier has a daughter from a previous relationship named Sherryl Brown-Tubbs. He later married Bernice Lewis, who had one child, Denise, whom he adopted before he and Lewis divorced. He then married Margie Grier and had a son, Roosevelt Kennedy Grier, in 1972. He and Margie divorced in 1978 and remarried in 1980. Margie Grier died on June 10, 2011. He married Wichita school teacher Cydnee Seyler on April 30, 2013. A nephew, Mike “Big Daddy” Grier, followed his uncle’s career in sports when he enrolled as a student at Boston University, but he played ice hockey instead of football.

He has been honored by Penn State as recipient of the Distinguished Alumni Award in 1974, and the Alumni Fellow Award in 1991. He was named to the NCAA’s “List of the 100 Most Influential Student-Athletes” published to commemorate the NCAA’s 100th anniversary. In 1997, he was inducted into the New Jersey Sports Hall of Fame.

Grier sang the song “It’s All Right to Cry” for the children’s album and TV program Free to Be… You and Me. Grier appeared on the television game show Match Game 74 as a panelist. Grier starred in television shows and films including The Wild, Wild West (1967), Desperate Mission (1969), Carter’s Army (1970), Skyjacked (1972), The Thing with Two Heads (1972), McMillan & Wife (1974), The Treasure of Jamaica Reef (1975), Movin’ On (1975-1976), CHiPs (1977), The Glove (1979), Roots: The Next Generations (1979) and The Seekers (1979). Grier appeared in the 1974–1976 NBC TV series Movin’ On with Claude Akins; it was filmed in Grier’s home state of Georgia. Greer appeared in a third-season episode of Quincy, M.E. called “Crib Job” in which he played himself as the director of a group called Giant Step. He appeared in two episodes of Kojak, one in the third season and one in the fourth season, as a bounty hunter called Salathiel Harms. He also appeared on an episode of CHiPs during its first season in 1977. He played a distraught motorist who, during a routine traffic stop, proceeds to destroy his car in frustration by pulling it apart piece by piece. He appeared as a celebrity contestant on Celebrity Bullseye during that program’s 1981–82 season. Grier also guest-voiced a 1999 episode of The Simpsons titled “Sunday, Cruddy Sunday”.

Grier has also written a number of books, and now travels the United States as an inspirational speaker. He is a cofounder of American Neighborhood Enterprises, an organization that works to help disadvantaged city dwellers buy homes and receive vocational training. Grier was ordained a Protestant minister in 1983, and the next year he founded his nonprofit resource center for inner-city teens, developing spiritual and educational programs for disadvantaged youths.

Grier released his autobiography Rosey: The Gentle Giant in 1986.

In 2017, he was inducted into the New Jersey Hall of Fame.

On January 5, 2017, Grier announced his intention to run for governor of California as a Republican in the California gubernatorial election, 2018. He ended his candidacy in July 2017.