He was a program Director and announcer at radio station WPOP in Hartford, Connecticut in the 1950s. He went on to work as a disc jockey, sometimes using the moniker "Doc" Downey, in various markets around the U.S., including Phoenix (KRIZ), Miami (WFUN), Kansas City (KUDL), San Diego (KDEO) and Seattle (KJR). Like his father, Downey pursued a career in music, recording in both pop and country styles. He sang on a few records and then began to write songs, several of which were popular in the 1950s and 1960s. He joined ASCAP as a result. In 1958, he recorded "Boulevard of Broken Dreams", which he sang on national television on a set that resembled a dark street with one street light. In 1981, "Green Eyed Girl" charted on the Billboard Magazine country chart, peaking at #95.

Downey was married four times and had four children from three of those marriages. With wife Helen, he had daughter Melissa; with Joan, he had daughters Tracey and Kelli; and, with fourth wife Lori, he had daughter Seanna Micaela. He and Lori met when she appeared as a Dancer in a show he attended in Atlantic City. According to Terry Pluto's book, Loose Balls, Downey was one of the owners of the New Orleans Buccaneers basketball team in the American Basketball Association in the late 1960s. Downey was also President and co-founder of the proposed World Baseball Association in 1974.

On January 22, 1980, Downey, a devoted pro-life Activist, hosted the California State Rally for Life at the invitation of the California ProLife Council and United Students for Life. At that time, he was also running for President of the United States, as a Democrat. The United Students for Life, at California State University, Sacramento helped organize his California presidential rallies. Downey worked to help promote pro-life candidates in California and around the country.

In 1984, at KFBK radio, Downey used the word "Chinaman" while telling a joke. His use of the word upset portions of the sizable Asian community in Sacramento. One Asian-American city councilman called for an apology and pressured the station for Downey's resignation. Downey refused to apologize and was forced to resign with Rush Limbaugh taking his place.

Downey headed to Secaucus, New Jersey, where his highly controversial television program The Morton Downey Jr. Show was taped. Starting as a local program on New York-New Jersey superstation WWOR-TV in October 1987, it expanded into national syndication in early 1988. The program featured screaming matches among Downey, his guests, and audience members. Using a large silver bowl for an ashtray, he would chainsmoke during the show and blow smoke in his guests' faces. Downey's fans became known as "Loudmouths," patterned after the studio lecterns decorated with gaping cartoon mouths, from which Downey's guests would go head-to-head against each other on their respective issues.

In April 1988, he was arraigned on Criminal charges for allegedly attacking a gay guest on his show, in a never-aired segment. In another lawsuit, he was accused of slandering a newscaster (a former colleague), and of indecently exposing himself to her and slapping her. Downey punched Stuttering John during an interview done for The Howard Stern Show, while also shouting Verbal insults at John, referring to him as an "uneducated slob". The situation then began to evolve into a brawl between the two until Downey had to be pulled off of John by security; the entire incident was caught on camera. When an Inside Edition camera crew approached Downey in 1989 to question him about his involvement in an alleged Business scam, Downey grabbed the boom mike and struck the soundman's head with it.

In late April 1989, he was involved in an incident in a San Francisco International Airport restroom in which he claimed to have been attacked by neo-Nazis who painted a swastika on his face and attempted to shave his head. Some inconsistencies in Downey's account (e.g., the swastika was painted in reverse, suggesting that Downey had drawn it himself in a mirror), and the failure of the police to find supportive evidence, led many to suspect the incident was a hoax and a ploy for attention. In July 1989, his show was canceled, with the owners of the show announcing that the last episode had been taped on June 30, and that no new shows would air after September 15, 1989.

In 1990, Downey resurfaced on CNBC with an interview program called Showdown, which was followed by three attempted talk radio comebacks: first in 1992 on Washington, D.C. radio station WWRC; then in 1993 on Dallas radio station KGBS, where he would scream insults at his callers. He was also hired as the station's VP of Operations. The following year, he returned to CNBC with a short-lived television show, Downey; in one episode, Downey claimed to have had a psychic communication with O.J. Simpson's murdered ex-wife, Nicole Brown Simpson.

On August 30, 1997, Downey quit his WTAM show to focus on pursuing legal action against Howard Stern. Downey had accused Stern of spreading rumors that he had resumed his smoking habit, to which publicist Les Schecter retorted, "He hasn't picked up a cigarette." His replacement was former WERE host Rick Gilmour.

In 1998, a Golden Palm Star on the Palm Springs, California, Walk of Stars was dedicated to him.

In June 1996, Downey was diagnosed with lung cancer while being treated for pneumonia, and had one of his lungs removed. He did a complete about-face on the issue of tobacco use, going from a one-time member of the National Smokers Alliance to a staunch anti-smoking Activist. He continued to speak against smoking until his death from lung cancer and pneumonia on March 12, 2001.

Following his death, news reports and obituaries incorrectly (according to the Orange County Register) credited him as the Composer of "Wipe Out." As of 2008, Downey's official website (and others) continue to make this claim. Prior to Downey's death, Spin in April 1989 had identified the Wipe Out authorship as a myth.

Released in 2012, the documentary film Évocateur: The Morton Downey Jr. Movie touches upon Downey's upbringing and formative years in radio and politics before launching into the history of The Morton Downey Jr. Show and Downey's influence on trash TV. The film also looks at Downey's relationship with Al Sharpton and other important 80s figures, as well as Downey's role as a predecessor for commentators like Glenn Beck and Rush Limbaugh.

His third – and final – attempt at a talk radio comeback occurred in 1997 on Cleveland radio station WTAM in a late evening time slot. It marked his return to the Cleveland market, where Downey had been a host for crosstown radio station WERE in the early 1980s prior to joining KFBK. This stint came shortly after the surgery for lung cancer that removed one of his lungs. At WTAM, Downey abandoned the confrontational schtick of his TV and previous radio shows, and conducted this program in a much more conversational and jovial manner.