During a January 1985 blizzard, he recommended to Buffalo residents "go home, buy a six pack of beer, and watch a good football game."

While mayor, he was the unsuccessful Republican nominee for Erie County executive in 1991, losing to incumbent Dennis Gorski.

In 1996, Griffin sought the Democratic nomination for president in the New Hampshire primary, finishing a very distant eighth to Bill Clinton.

After the "Spring of Life" demonstration in April 1992 where Griffin encouraged pro-life groups such as Operation Rescue to protest in Buffalo, he declined to seek a fifth term as mayor and was succeeded by Democrat Anthony Masiello.

He then unsuccessfully sought a seat in the New York State Assembly against future Congressman Brian Higgins (where Griffin was defeated in his home base of South Buffalo for the only time in his elector career) and was rumored to have an interest in a seat in the Erie County Legislature that was vacated in 2001, although in the end he did not run.

In 1996, Griffin entered the New Hampshire Democratic Presidential Primary election, finishing well behind incumbent Bill Clinton, and even garnering fewer votes than perennial candidate and satirist Pat Paulsen.

However, on July 17, 2007, Griffin announced that he was joining the race for the Erie County Executive seat, against fellow South Buffalonian and endorsed Democratic Party candidate Jim Keane.

Griffin later endorsed the candidacy of Republican candidate and with the assistance of his group of campaign volunteers, helped Christopher C. Collins win the election for Erie County Executive.

Following his death, the Buffalo Common Council voted to rename the address of Sahlen Field to One James D. Griffin Plaza in his honor.