Seventh-ranked Del Potro, the 2009 US Open champion from Argentina, defeated German third seed Tommy Haas 7-6 (4), 6-3 while Isner blasted 29 aces in a 6-7 (7), 6-3, 6-4 victory over Russia’s Dmitry Tursunov.
Del Potro, the 2008 and 2009 Washington winner, was down 1-4 when rain halted the first set for more than three hours, but won the next four games once play resumed.
“The rain delay helped me play much better in the second part of the match,” Del Potro said. “I came back with too much power on my forehand. It was too much for Tommy.”
Del Potro saved a set point with a second-serve ace in the 12th game and took the tie-breaker when Haas hit a backhand long.
Haas netted a backhand to surrender a break in the eighth game of the second set and Del Potro held for the victory, stretching his win streak to 13 matches at the $1.76 million hardcourt event, having not played in the US capital since his title run four years ago.
Haas fell to 0-5 against Del Potro and has never taken a set from the South American star.
Isner, who won last week in Atlanta, took the only break of his second set on the first point after a rain delay of more than an hour in the fourth game, hitting a forehand winner.
In the final set, Isner broke at love in the fifth game, fired four aces in a row to sweep the final game and 10 aces overall.
Isner, ranked 20th, tops the season ATP rankings in aces with 587 in 37 matches and has a tournament-best 78 aces this week.
Del Potro, playing his first event since losing an epic Wimbledon semi-final to top-ranked Novak Djokovic, seeks his 15th career ATP crown and second of the year after Rotterdam in February. His most recent final was at Indian Wells, where he lost to Rafael Nadal.
Isner seeks his eighth career ATP title and third crown of the year, having also won in April at Houston.