The men's top seed fell to qualifier Ivo Karlovic, 1-6, 7-6 (7-5), 6-3, 6-4, in the first match on Centre Court.
"At the end of the day, I'd be disappointed losing in the first round at Wimbledon at any time," said Hewitt.
Hewitt had not lost in the first round in the Open Era, which began in 1968. It happened once before when Manuel Santana lost to Charlie Pasarell in four sets in 1967.
Karlovic, a native of Croatia, who is 6-10 and ranked 203rd in the world, recovered after looking overwhelmed in losing the first set in just 19 minutes.