Frank Mentzer was born in a suburb of Philadelphia, the older of two children (his sibling is Susanne Mentzer). In high school, he started to play folk music, and at age sixteen, he played his first paid folk music concert at the opening of the Visitors' Center for the Liberty Bell and Independence Hall in downtown Philadelphia. Immediately after Mentzer graduated from high school, his father, who worked for the National Park Service (NPS), moved the family to Maryland in order to work at Catoctin Mountain Park. Mentzer was interested in furthering his folk music career, and with his father's advice on who in the NPS to contact, Mentzer was able to arrange to play concerts in at various NPS sites. In 1972, he was hired by NPS to play a public concert in the White House gardens for inner-city children. At one point in the concert Pat Nixon, followed by national news crews, came to listen, and a clip of Mentzer singing "If I Had a Hammer" subsequently appeared on national newscasts that evening. Mentzer moved back to the Philadelphia area, and for a short time during the 1970s, he worked as the manager of a pinball arcade.

In the mid-1970s, Mentzer and a friend taught themselves how to play the new role-playing game Dungeons & Dragons, and he became part of a group of 8—12 players who played several times a week. In 1979, TSR, the company that published D&D, advertised for a designer and an editor. Although Mentzer was initially uninterested since he had no editorial or design experience, fellow player David Axler...who would go on to write an article for the December 1981 issue of Dragon magazine about how to determine the weather in the World of Greyhawk campaign setting...urged him to apply, and Mentzer finally relented. After a phone interview with TSR, Mentzer was hired for the editorial position...Tom Moldvay was hired as the new designer...and in January 1980, Mentzer moved to Lake Geneva, Wisconsin.

Soon after joining TSR, he was invited to participate in TSR's first "DM Invitational", a contest to choose D&D's best overall dungeon master. (Other contestants included Len Lakofka and Erol Otus.) At Gen Con 1980, Mentzer was announced as the winner, and was awarded a silver cup and a gold dragon chain of office. Mike Carr of TSR had been contemplating starting a TSR-sponsored D&D fan club. Shortly after Mentzer won the DM Invitational, Carr approached him about taking on that task. Mentzer agreed to form some sort of group, but rather than a simple "fan club", he was interested promtoing better quality roleplaying, especially during scored D&D events at conventions. Mentzer felt that the system as it stood rewarded those players that stayed quiet at the table, in effect punishing good roleplayers. He came up with a scoring system where the dungeon master and the players all voted on who had been the best roleplayer at the table. With this in place, Mentzer formed the RPGA, an organization that would promote quality roleplaying and allow fans of roleplaying games to meet and play games with each other. Mentzer wrote four RPGA tournament adventures taken from his home campaign setting of "Aquaria" (published by TSR as the first four of the R-series modules: R1 To the Aid of Falx, R2 Investigation of Hydell, R3 Egg of the Phoenix, and R4 Doc's Island). Mentzer envisioned them as becoming a part of Gary Gygax's World of Greyhawk setting, the first part of a new "Aqua-Oeridian" campaign set somewhere on Oerth outside of the Flanaess. (The connection between Aquaria and Greyhawk was never made, but these four modules were later revised by Mentzer and Paul Jacquays and re-published as the "super-module" I12 Egg of the Phoenix in 1989.)

Mentzer became involved with the auction of hobby gaming materials at Gen Con in 1983, and has been involved with what is now called the world's largest game auction every year since then.

Mentzer was soon promoted to Creative Director at TSR, and one of the tasks he was given was to collate and revise the various rules sets for Basic D&D in such a way as to not borrow any rules, monsters or other material that had been developed specifically for Advanced Dungeons & Dragons (AD&D). This resulted in the Basic (1983), Expert (1984), Companion (1984), Master (1985), and Immortals (1986) boxed sets of D&D rules (collectively known as BECMI). These were eventually translated into 11 languages, and millions were sold worldwide.

Other work by Mentzer included IM-1 The Immortal Storm (1986), I-11 Needle (1987), and an adventure module for TSR's Star Frontiers game based on Arthur C. Clarke's novel A Space Odyssey. Because of his work with the Gen Con game auction, Mentzer had become interested in the game memorabilia market, resulting in The Game Buyers' Price Guide 1986, which summarized current market prices for hobby games. (Further annual editions were planned, but when Mentzer left TSR, this project was shelved.)

He also worked closely with Gary Gygax, and co-wrote the adventure module T1-4 The Temple of Elemental Evil (1985), and the accessory The Book of Marvelous Magic (1985).

In late 1985, Gary Gygax and Lorraine Williams vied for control of TSR, which eventually resulted in Gygax's ouster. Mentzer, who had worked closely with Gygax for six years and shared his vision of the direction for D&D, was unwilling to work for Williams, and left TSR in 1986.

Gygax quickly formed New Infinities Productions, Inc. (NIPI) to create new products for the role-playing game market, and Mentzer joined as Design Executive. Mentzer, together with Gygax and Kim Mohan, formed the Creative Committee.

The company's first product was the science fiction-themed Cyborg Commando, co-written by Mentzer and Gygax, and published in 1987. The next project a was a new fantasy role-playing game spanning multiple genres called Dangerous Journeys. (It was originally to have been called Dangerous Dimensions, but the name was changed to Dangerous Journeys in response to a threat of a lawsuit from TSR, Inc. that the DD abbreviation would be too similar to "D&D.") When the product was released by Game Designers' Workshop, TSR immediately sued for copyright infringement. The suit was eventually settled out of court, with TSR buying the complete rights to the Dangerous Journeys system from New Infinities and then permanently shelving the entire project. This led to the demise of NIPI, and Mentzer decided to leave the game industry.

For some years afterwards, Mentzer did a bit of writing, including Cooking Without Fire with Paul Kamikawa (1992), and "Trust at the Gaming Table", part of the Origins Award-winning Game Master Secrets Vol. II (Grey Ghost Press, 2003). He also became a collector of hobby games, and an expert on their worth at auction.

In 2000, he and his second wife Debbie moved to Minocqua, Wisconsin and opened a bakery, his wife becoming the baker while Mentzer acted as manager. This operation eventually expanded to include three bakeries. However, running the bakeries was time-consuming, and faced with other demands on their lives, the Mentzers decided to shut down their bakeries in 2008 and move to Rockford, Illinois.

In 2010, Mentzer announced that he was going to form a new publishing company for role-playing games, and expected to make an official announcement in October 2010.