The news was confirmed by Nickelodeon, which has broadcast the hugely popular cartoon series since 1999.
In a statement, the company said Hillenburg's cause of death was motor neurone disease (also known as ALS) - a condition he revealed he had been diagnosed with in March last year.
As well as creating the character, Hillenburg also directed 2004's The SpongeBob SquarePants Movie.
"We are sad to share the news of the passing of Stephen Hillenburg, the creator of SpongeBob SquarePants," Nickelodeon tweeted from its official account.
"Today, we are observing a moment of silence to honour his life and work."