Danny Espinosa tied the game with a round-tripper off Addison Reed and Kevin Frandsen launched a go-ahead, pinch-hit shot off the closer that gave the Nationals a 6-5 decision in the opener of this three-game series.
Washington hit four homers in the victory, with Tyler Moore and Ian Desmond each going deep to help the club shake off dropping three straight games in Oakland over the weekend.
Reed (1-3) was saddled with his second blown save of the year, while Tyler Clippard (3-2) picked up the win with a scoreless inning of relief.
Rafael Soriano erased a leadoff single in the home ninth with a double-play ball off the bat of Eric Chavez and survived Gerardo Parra's double to secure his eighth save and send the Diamondbacks to their 16th loss in 19 home games.
Josh Collmenter surrendered four runs on four hits in his five-inning start for Arizona, and his counterpart, Jordan Zimmermann, gave up five runs on 10 hits over 5 2/3 innings.
Nationals manager Matt Williams returned to Chase Field after being part of Arizona's coaching staff the previous four seasons and saw his team jump out to a quick 1-0 lead when Denard Span led off the game with a single and scored on Anthony Rendon's sacrifice fly.
Moore made it 2-0 with a solo blast in the second before the D-backs answered with three runs -- all with two outs -- in the third.
Collmenter recorded his first career two-bagger with one away, and after Parra struck out, Martin Prado and Paul Goldschmidt each laced doubles to score runs. Miguel Montero capped the frame with an RBI single.
Desmond's two-run blast in the fourth staked the Nationals to a 4-3 lead, but A.J. Pollock countered two innings later with a two-run blast of his own that landed in the pool beyond the wall in right-center.