Most of the music Rzeznik listened to while growing up was influenced by his sisters, and consisted of classic rock such as The Rolling Stones and The Kinks. The youngest of his four older sisters moved towards punk music and Rzeznik became interested in bands such as the Ramones and The Clash. Rzeznik attributes his gift for melody to listening to bands such as Kiss, Cheap Trick, The Cure and Rush in the early 1980s. Rzeznik also cites Paul Westerberg as an "obvious influence" on his music. Westerberg co-wrote the 1993 Goo Goo Dolls song "We Are the Normal" with Rzeznik, who reflected on the experience by stating "To some people, Keith Richards is their hero. I feel that way about Westerberg. Keith Richards got to do his thing with Chuck Berry, and I got to do it with Westerberg. That was amazing to me."

Rzeznik's father died on February 2, 1981, from a diabetic coma at the age of 55, when Rzeznik was 15 years old. On October 26, 1982, his mother died from a sudden heart attack in the family's living room at the age of 53. Having lost both of his parents, he was brought up by his four older sisters, Phyllis, Fran, Gladys and Kate, with help from their cousin John Guljas. He paid for his own apartment using Social Security Survivor Benefit checks. It was during this period and while attending McKinley Vocational High School that Rzeznik began playing the guitar. Rzeznik briefly attended Buffalo State College, dropping out after his first year.

In 1985, he formed the band that became the Goo Goo Dolls with Robby Takac. Previously John had been in a band with Takac's cousin, called The Beaumonts. It is thought the band was originally called The Sex Maggots, however Rzeznik admitted this was a joke on stage one night, and he was "never actually in a band called The Sex Maggots". They got the name Goo Goo Dolls from an ad in a True Detective magazine when a concert promoter asked them.

After having their equipment stolen from a van in New York City (which included Rzeznik's Marshall JCM 800 amplifier and his only guitar at the time), following the recording of their 1989 album, Jed, a custom, yellow Stratocaster-style guitar (later nicknamed "Boing") was made for Rzeznik by ESP. Now without an amplifier, Rzeznik borrowed a near-identical Marshall JCM 800 from a mutual friend of the band, Charles Root. This Marshall JCM 800 was then used to record Hold Me Up and Superstar Car Wash. Since the late '90s, Rzeznik has used Fender electric guitars. He has used many variations such as the Stratocaster, Telecaster, Jaguar and a "Halfcaster" (a Stratocaster cut in half). He also used Guild acoustic guitars on the "Dizzy Up the Girl" and "Gutterflower" tours. Rzeznik in a 2003 interview noted that "No matter what guitar I have it seems that anything with strings makes music to my ears." Guild Models used include several D-55s (unusually, most of his D-55s were built in Fender's Corona, California Shop), a black F65CE, multiple Peregrine/S7CE Customs (a Guild Custom Shop Model), a black Songbird/S4CE, and a black F47M. Live performances of this time sometimes showed the auxiliary Guitarist, Greg Suran, using some Guild acoustics such as the DV-52 and F-47M in natural finishes.

On July 4, 2004, Rzeznik and his bandmates returned home to Buffalo and played a free show to give back to their loyal fans, over 60,000 of whom attended. The day quickly became a city triumph when rain came pouring down during their performance. It turned out to be one of the strongest rain storms of the year in Buffalo, but the Goo Goo Dolls did not stop playing. Rzeznik declared, "We're going to keep going until this shit stops". This performance was captured on DVD and CD for the public in the Goo Goo Dolls release Live in Buffalo: July 4, 2004.

From October to December 2007, Rzeznik was a judge alongside Sheila E. and Australian Idol judge and marketing manager Ian "Dicko" Dickson on the Fox network's The Next Great American Band.

On June 19, 2008, John Rzeznik was inducted into the Songwriters Hall of Fame and was awarded the Hal David Starlight award.

Rzeznik met former model Laurie Farinacci in 1990, married her in 1993 but got a divorce in 2003; they did not have any children. He started dating Melina Gallo in 2005 and married her in Malibu, California, on July 26, 2013. On December 22, 2016, he and Gallo had their first child, a daughter, Liliana.

On March 24, 2014, Cash Cash released their new single "Lightning" which features John Rzeznik on vocals and was written by Cash Cash and Rzeznik together.

On April 18, 2015, he participated in the Toyota Celebrity/Pro Race where he finished 12th to actor and former two-time winner of the event Alfonso Ribeiro for which he donated $5,000 to charity.