His spokesperson said Inouye passed away today Monday after being hospitalized for respiratory complications.
The Democrat was elected in 1962 and has been a Senator for all but three of Hawaii's 53 years as a state.
After losing his right arm in battle during World War Two, Inouye was awarded the Medal of Honor and was a champion for veterans rights.
Inouye was the second-longest serving Senator in American history, trailing only Senator Robert Byrd of West Virginia.
He was 88 years old.
The senator's office says his last word was "Aloha".