The 62-year-old drummer - who joined the Jeremy grunge rock band in 1998 after Jack Irons left mid-tour after the release of Yield - has confirmed his departure after "an incredible journey".
"After 27 fantastic years, I have taken my final steps down the drum riser for the mighty Pearl Jam," he said in a post on Instagram.
"Much love and respect to Jeff (Ament), Ed(die Vedder), Mike (McCready) and Stone (Gossard) for inviting me into the band in 1998 and for giving me the opportunity of a lifetime, one filled with friendships, artistry, challenges and laughter.
"I am forever grateful to the crew, staff and fans the world over. It's been an incredible journey.
"More to follow. Thank you all from the bottom of my heart."
Cameron - who has also been a member of Soundgarden since 1986 - is yet to reveal the reason for his departure, or his plans.
However, the remaining members of Pearl Jam insisted he "will be deeply missed".
In their own statement, they added: "From being one of our first musical heroes in the bands Skinyard and the mighty Soundgarden, to playing on our first demos in 1990, Matt Cameron has been a singular and true powerhouse of a musician and drummer.
"He has propelled the last 27 years of Pearl Jam live shows and studio recordings. It was a deeply important chapter for our group and we wish him well always.
"He will be deeply missed and is forever our friend in art and music. We love you Matt."
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