At age 12, Arnaz was a drummer with Dino, Desi, & Billy. The others were Dean Paul Martin (son of Dean Martin) and Billy Hinsche. The band scored two hit singles with “I’m a Fool” and “Not the Lovin’ Kind” in 1965.

From 1968 to 1974, Desi Arnaz and his sister Lucie co-starred opposite their mother in Here’s Lucy as her children. In 1968, he had a guest-starring role as Jerry and Suzie’s drum-playing friend Tommy in the episode, “The Hombre Who Came to Dinner: Part 2,” from the show The Mothers-in-Law, executive-produced and directed by his father. In 1970, he appeared on The Brady Bunch episode “The Possible Dream.” His best chance at enduring Hollywood fame came in 1973, when he played the title role in the film “Marco,” a musical about the life of adventurer Marco Polo. However, like most Hollywood musicals of that period, it failed to register at the box office.

Arnaz has a daughter, Julia Arnaz, from a relationship with model, Susan Callahan-Howe, in 1968 when they were both 15 years old; Julia’s relationship to Desi Jr. was proven by a paternity test in 1991.

Arnaz was subsequently involved with entertainer Liza Minnelli, another relationship of which his mother disapproved; Ball thought that the singer-actress was too old for her son and, because of Liza’s perceived reckless lifestyle, not a good influence upon him. Arnaz accompanied Minnelli to the Academy Awards ceremony in March 1973 when she won the Academy Award for Best Actress.

In 1974, Arnaz played the title role in the Western movie Billy Two Hats with Gregory Peck. In 1976, he appeared on two episodes of the television series, The Streets of San Francisco. Arnaz also appeared in a 1976 episode of Saturday Night Live (SNL) hosted by both Desi Arnaz and Desi Arnaz Jr.. The younger Arnaz played Ricky Ricardo while Gilda Radner played Lucy in spoofs of supposed ill-fated pilots for I Love Lucy. Although a part of I Love Lucy for the purpose of these SNL parodies, he did not portray Little Ricky in the classic sitcom, a role played instead by Keith Thibodeaux (Richard Keith (actor)).

In 1977, he was the lead in the film Joyride opposite fellow children of famous actors Melanie Griffith, Robert Carradine, and Anne Lockhart.

Arnaz married actress Linda Purl in 1979. On January 3, 1980, Purl filed for divorce, which was finalized later that year. On October 8, 1987, Arnaz married Amy Laura Bargiel. In 1997, Arnaz purchased the Boulder Theatre in Boulder City, Nevada and restored it, when it had been on the brink of ruin. The cinema was converted to a theatre and home to the Boulder City Ballet Company. They also lived in Boulder with their daughter, Haley.

In 1992, he played his father in the movie The Mambo Kings, based on a Pulitzer Prize-winning novel that he felt treated his father with respect. The film includes a scene in which Desi Jr., playing his father’s character Ricky Ricardo, acts opposite his mother as Lucy Ricardo with film from the TV series intercut with the cast.

Between 1998 and 2010, he was touring with a new configuration of Dino, Desi & Billy called Ricci, Desi & Billy, featuring Arnaz reunited with Billy Hinsche, and joined by Ricci Martin (youngest son of Dean Martin). The group performs original material as well as the songs the original band performed.

From about 2002 to 2007, he was vice-president of the board of Directors of the Lucille Ball–Desi Arnaz Center in Jamestown, New York. He resigned over a dispute with the executive director over the center.

In 2007, Arnaz appeared at the 5th Annual TV Land Awards with his sister Lucie to accept the Legacy of Laughter award posthumously given to their mother.

On October 15, 2011, Arnaz performed in Babalu at the Coolidge Auditorium of the Library of Congress. The performance was in conjunction with the Library’s Lucille Ball and Desi Arnaz Collection.

Desi’s wife Amy died of cancer in 2015, at the age of 63. Both Desi and Amy were followers of Vernon Howard and attended meetings of Howard’s New Life Foundation in Boulder City. They also followed and have supported the spiritual writer Guy Finley (also one of Vernon Howard’s students) and his Life of Learning Center for Spiritual Discovery.

Arnaz’s granddaughter (daughter of Julia) Desiree S. Anzalone, a photographer, died from breast cancer on September 27, 2020 at the age of 31. She was first diagnosed with cancer when she was 25.