"It's been a wonderful time and how great for me to finish up my broadcasting of games in Houston," Hamilton said Wednesday.
This will be the 84-year-old Hamilton's 28th year with the Astros and 59th year overall calling Major League Baseball games.
"He's been an icon broadcaster," new Astros owner Jim Crane said. "He's one of the greatest ever and has a history that's probably second to not many. He's meant a lot to the organization."
He will remain with the team after this season working mostly on special events but will make sporadic appearances on radio broadcasts.
Hamilton's time calling the majors is second all-time only to Vin Scully, who is entering his 64th season.
He was inducted into the broadcasters wing of the National Baseball Hall of Fame in 1992 and the Radio Hall of Fame in 2000.
"When you hear his voice, you think of the Astros," Crane said. "There's not many teams where when you hear someone's voice, you immediately think of that ball club. His history speaks for itself."
Hamilton made the call on Aaron's 715th home run on April 8, 1974, as a broadcaster for the Atlanta Braves. He said that was the highlight of his career.
"The Aaron home run made it a great call because it barely made it," Hamilton said. "It wasn't like Mark McGwire's going over the McDonald's sign at Busch. I still enjoy it when I hear it."
He has also called 11 no-hitters, Nolan Ryan's 4,000th strikeout in 1985 and Craig Biggio's 3,000th hit in 2007. He also called the Pirates 1979 championship season and when Stan Musial hit five home runs in a doubleheader.
He said his most memorable no-hitter was Mike Scott's division-clinching one in 1986, and Hamilton said Biggio's 3,000th hit was another high point of his career.
"That's pretty cool," Biggio said. "Considering the guy called Hank Aaron's home run and the many other things he called and for him to think that me getting 3,000 hits was one of the highlights of his career also was just a huge honor."
Hamilton has called more than 4,000 spring training, regular-season and playoff games. He stopped traveling with the team in 2006 but occasionally makes road trips. He will broadcast Houston's series against the Miami Marlins from April 13-15, which will be the 59th ballpark he's broadcast from.
He hopes to return to the booth next season when the Astros move to the American League and visit Detroit, so he can mark that park off the list.
The Astros will honor him with "Milo Hamilton Day" on his 85th birthday Sept. 2.