Ramis was born on November 21, 1944, in Chicago, Illinois, the son of Ruth (née Cokee) and Nathan Ramis, who owned the Ace Food & Liquor Mart on the city’s far North Side. Ramis had a Jewish upbringing. In his adult life, he did not practice any religion. He graduated from Stephen K. Hayt Elementary School in June 1958 and Nicholas Senn High School in 1962, both Chicago public schools, and in 1966 from Washington University in St. Louis, Missouri, where he was a member of the Alpha Xi chapter of Zeta Beta Tau fraternity.

Ramis was married twice and fathered four children. On July 2, 1967, he married San Francisco artist Anne Plotkin, with whom he had a daughter, Violet Ramis Stiel. Actor and Ghostbusters co-star Bill Murray is Violet’s godfather. Ramis and Plotkin separated in 1984 and later divorced. In 1985, Ramis had daughter Mollie Heckerling with director Amy Heckerling. In 1989, Ramis married Erica Mann, daughter of director Daniel Mann and actress Mary Kathleen Williams. Together they had two sons, Julian Arthur and Daniel Hayes in 1990 and 1994. Although Ramis maintained Humanist beliefs, Erica’s Buddhist upbringing was a huge influence on his philosophies for the rest of his life, and he became friends with the Dalai Lama.

After leaving Second City for a time and returning in 1972, having been replaced in the main cast by John Belushi, Ramis worked his way back as Belushi’s deadpan foil. In 1974, Belushi brought Ramis and other Second City performers, including Ramis’ frequent future collaborator Bill Murray, to New York City to work on The National Lampoon Radio Hour.

He also had a voice part as Zeke in the “So Beautiful & So Dangerous” segment of Heavy Metal in 1981.

In 1982, Ramis was attached to direct the film adaptation of the Pulitzer Prize-winning book A Confederacy of Dunces by John Kennedy Toole. The film was to star John Belushi and Richard Pryor, but the project was aborted. In 1984, Ramis collaborated with Dan Aykroyd on the screenplay for Ghostbusters, which became one of the biggest comedy hits of all time, in which he also starred as Dr. Egon Spengler, a role he reprised for the 1989 sequel, Ghostbusters II (which he also co-wrote with Aykroyd). His later film Groundhog Day has been called his “masterpiece.”

In 1984, Ramis executive produced a music/comedy/variety television show called The Top. The producer was Paul Flattery and the director was David Jove. Ramis got involved after the mysterious death of his friend Peter Ivers who had hosted Jove’s underground show “New Wave Theater.” He called Jove and offered to help. Flattery and Jove pitched him the idea for The Top, and Ramis was instrumental in getting it on the air.

In 2004, Ramis turned down the opportunity to direct the Bernie Mac-Ashton Kutcher film Guess Who, then under the working title “The Dinner Party,” because he considered it poorly written. That same year, he began filming the low-budget The Ice Harvest, “his first attempt to make a comic film noir.” Ramis spent six weeks trying to get the film greenlit because he had difficulty reaching an agreement about stars John Cusack’s and Billy Bob Thornton’s salaries. The film received mixed reviews. In 2004, Ramis’s typical directing fee was $5 million.

In 2004, Ramis was inducted into the St. Louis Walk of Fame. In 2005, he received the Austin Film Festival’s Distinguished Screenwriter Award. In 2010, he received a lifetime achievement award from the Chicago Improv Festival. In 2015, the Writers Guild of America posthumously honored him with their lifetime achievement award, the Laurel Award for Screenwriting Achievement.

Ramis said in 2009 that he planned to make a third Ghostbusters film for release either in mid-2011 or for Christmas 2012. The film was eventually made and released in 2016, although directed and co-written by Paul Feig, not Ramis. In this film, a bronze bust can be seen of Ramis when Erin Gilbert leaves her office at Columbia University.

In May 2010, Ramis contracted an infection that resulted in complications from autoimmune inflammatory vasculitis and lost the ability to walk. After relearning to walk he suffered a relapse of the disease in late 2011.

He died of complications of the disease on February 24, 2014, at his home on Chicago’s North Shore, at age 69. A private funeral was held for him two days later with family, friends, and several collaborators in attendance, including Dan Aykroyd, Chevy Chase, Eugene Levy, Dave Thomas, David Pasquesi, Andrew Alexander, and the widows of John Belushi and Bernard Sahlins. He is buried at Shalom Memorial Park in Arlington Heights.

In 2016, two years after his death, The Second City founded the Harold Ramis Film School, the first film school to focus solely on film comedy, in his honor.

The 2016 film Ghostbusters, a reboot of the series Ramis co-created and starred in, was posthumously dedicated to him. A bust of his head appears in the film.