Pujols, 34, became the 26th major league player to reach the milestone, doing it in style at Nationals Park.
The Dominican belted his 499th homer at the top of the first inning, to put the Angels 3-0 up in Washington.
Pujols then brought up homer number 500 on a line drive to centre field, for a two-run blast that brought his team-mates to their feet.
The former St Louis Cardinals hero understood he was in elite company after reaching the mark.
"It's pretty special," Pujols said.
"To have almost 18,000 players wear a big league uniform, and to have only 26 players do this, it's pretty special.
"At the end, I give all the glory and all the credit to the Lord, because without him, I wouldn't be here.
"And my family, which supports me through good times and bad times."
The win saw the Angels to a 10-10 record, and sealed consecutive wins for the franchise, while the Nats have lost two in succession to have an 11-10 win-loss ledger.
The New York Yankees and Toronto Blue Jays both had 9-3 wins to consolidate first and second spot in the American League's East division.
The Yankees crushed rivals the Boston Red Sox via 15 hits, with former Red Sox hitter Jacoby Ellsbury marking his return to Fenway Park with two hits and as many RBIs.
The Blue Jays are one game behind the Yankees, after a trio of three-run blasts saw them fly past divisional rivals the Baltimore Orioles.
Edwin Encarnacion, Brett Lawrie and Melky Cabrera all struck the clutch homers, as they responded to a three-run blow from Baltimore's Nelson Cruz to sail to victory at their Rogers Centre home.
The Detroit Tigers sit top of the AL Central division, after an 8-6 win over the Chicago White Sox.
The Kansas City Royals are one game adrift of the Tigers, despite an 8-2 thrashing of the Cleveland Indians.
The Tampa Bay Rays were 7-3 victors over the Minnesota Twins, the Texas Rangers closed within half-a-game of the AL West-leading Oakland Athletics with a 5-4 win over their rivals and the Houston Astros inflicted the Seattle Mariners with their seventh straight loss via a 7-2 scoreline.
In the National League, East leaders the Atlanta Braves were felled 1-0 by the Miami Marlins.
It was the Marlins' first away win of the season at their eighth attempt.
The Braves remain 2.5 games clear of closest rivals Washington, while the New York Mets are three games back after they were humbled 3-0 by the St Louis Cardinals.
The Cardinals are three games behind NL Central leaders the Milwaukee Brewers, after the latter suffered a 2-1 loss to the San Diego Padres in extra innings.
The Cincinnati Reds were 4-1 winners over the Pittsburgh Pirates, the Chicago Cubs made it back-to-back wins with a 9-2 victory over the Arizona Diamondbacks, the Colorado Rockies trumped the San Francisco Giants 2-1 and the Philadelphia Phillies edged the Los Angeles Dodgers after a 10th inning.