Brandis got his show-biz break at the tender age of six when he landed a recurring role on "One Life to Live" and appeared in numerous commercials. He moved to Los Angeles with his family at age nine, and made guest appearances on shows such as "L.A. Law", "Who's the Boss?" and "Murder, She Wrote".

He received his first starring role in The NeverEnding Story II, and went on to appear primarily in television roles. Of these, he is most famous for his portrayal of scientific prodigy Lucas Wolenczak in Steven Spielberg's futuristic science fiction series seaQuest DSV. Also he is well known for voicing Mozenrath in Disney's Aladdin the television series, who resembles him somewhat.

During his lifetime he was romantically linked to Tatyana Ali, Heather McComb, Vinessa Shaw, and Monica Keena. He accompanied actress Brittany Murphy to her high school prom.

He expressed an interest in moving his career towards more directing work rather than acting, although he had auditioned for the role of Anakin Skywalker in George Lucas' Star Wars Episode II: Attack of the Clones.

On 12 November 2003, Brandis died from injuries he suffered after hanging himself the previous day. He was 27 years old. According to his mother, he went out to dinner with friends, then they went back to his apartment. His friends reported that he seemed to be agitated, and pacing around quite a bit. He left the room, and approximately 15 minutes later one of his friends went looking for him, and found him hanging by a nylon rope, in the second floor hallway of his building. His friends cut him down, and called paramedics. Despite efforts, he was pronounced dead at Cedars Sinai Medical Center. The Los Angeles Police Department released a statement about his death, as follows:

On November 11, 2003, at about 11:40 p.m., a friend of Jonathan Brandis called police to report that the actor had attempted suicide at his apartment, located in the 600 block of Detroit Avenue. Paramedics from the Los Angeles Fire department responded and transported Brandis to Cedars Sinai Medical Center where he eventually died from his injuries. Brandis was pronounced dead by hospital staff on November 12, 2003, at about 2:45 p.m." (). Jonathan apparently did not leave a note of any kind. According to his mother, he had no prior suicide attempts, drank socially, quit smoking over two years prior, and did not abuse drugs. There were no personal problems, except for the fact that he could be quite hard on himself. In a People magazine article, friends were quoted as saying he was lonely and depressed about his career lull. One friend said he knew Brandis drank heavily and had even told friends that he might kill himself. He was also said to be upset when his appearance in Hart's War, a role he hoped would be his comeback, ended up on the cutting room floor.