Minardos was married twice, first briefly in the mid-1950s to the former Deborah Jean Smith (sometimes incorrectly referred to as Deborah Ann Montgomery). There were no children from that marriage. Two years after the divorce, Deborah married the legendary actor Tyrone Power. Minardos remarried in 1965. He and his wife Julie had two children together, a son named George and a daughter named Nina. Minardos reputedly lived with the Actress Marilyn Monroe in the 1950s and also with the actress/dancer Juliet Prowse before she moved to Las Vegas to be with Frank Sinatra.

Nico Minardos made his first appearance in front of the Hollywood cameras as an extra in the 1952 film Monkey Business, starring Cary Grant, Ginger Rogers, and Marilyn Monroe. Also listed among his film credits are Holiday for Lovers with Jill St. John; Twelve Hours to Kill with Barbara Eden; It Happened in Athens with Jayne Mansfield; and Cannon for Cordoba, an action-packed western with George Peppard and Pete Duel.

The majority of Minardos's work, however, was in television, where he made guest appearances in a wide variety of shows. Because of his dark looks and accent, he was often cast as a Mexican, a trend which can be seen throughout his career. These roles included that of a thief in the Maverick episode, "The Judas Mask"; a Doctor in The Twilight Zone episode "The Gift"; and two roles in the TV show Alias Smith and Jones, first as a bandit chief in "Journey from San Juan," and then as the Alcalde of a Mexican resort town in "Miracle at Santa Marta." These latter two appearances reunited him with Cannon for Cordoba co-star, Pete Duel, who played Hannibal Heyes, the alias Smith of the title. He was cast as an Italian, Giangiacomo, in the 1965 Perry Mason episode "The Case of the Sad Sicilian."

On September 28, 1966, Minardos, who was co-starring with actor Eric Fleming in an MGM-TV movie filming on location in Peru to be called Selva Alta (High Jungle), was involved in a canoeing mishap on the Huallaga River in which Fleming drowned. Minardos, a strong Swimmer, was unable to rescue Fleming from the rapids and only barely survived himself. Fleming's body disappeared in the turbulent waters and was not recovered until three days later.

In 1975, Minardos starred in and produced Assault on Agathon based on the book by Alan Caillou. It is the story of a revolutionary from World War II, the mysterious Agathon, who is committing terrorist acts in Greece and Albania. Minardos stars as Cabot Cain, a Western agent assigned to stop Agathon and locate a missing Interpol agent. The film also starred Marianne Faithfull and John Woodvine. Minardos obtained financing for the film from Kjell Qvale, a Bay Area-based Automotive Entrepreneur who was then the majority shareholder in Jensen Motors. Minardos had approached Qvale for a product placement deal to use a Jensen Interceptor during filming but ultimately convinced Qvale to Finance the entire movie. MGM distributed the film but it was a financial failure. Minardos's last appearance on the screen was in an episode of The A-Team in 1983.

In 1986 Minardos was one of the celebrated defendants in a case related to the Iran-Contra Affair, resulting from Minardos' Business association with the Saudi arms merchant Adnan Khashoggi. Minardos was caught in an FBI sting operation in New York and was indicted by then-U.S. Attorney Rudy Giuliani on charges of conspiracy to illegally ship arms to Iran. He was represented by attorneys william Kunstler and Ron Kuby in this case. Minardos was interviewed by Mike Wallace for a segment of the CBS show 60 Minutes regarding his role in the case. Although the indictment was eventually thrown out, the cost of his legal defense drove him to the point of bankruptcy and also ended his Hollywood career. Minardos soon traded his home in Beverly Hills for a sailing yacht in Florida, which he subsequently outfitted and sailed across the Atlantic Ocean to his Greek homeland with a crew that included his son George.

Minardos retired to Fort Lauderdale, Florida, during the 1990s and 2000s, but moved back to Southern California in 2009 after suffering a stroke. He was the subject of a 2010 documentary about his life titled Finding Nico, which was produced and directed by his Godson, Owen Prell, whose father, Donald Prell, was a longtime friend of Minardos from their bachelor days in Los Angeles in the 1950s.