Henderson beat Slovenian rider Grega Bole and Jeremy Galland of France to complete the 201.5-kilometer (125-mile) flat stage in 4 hours, 22 minutes, 17 seconds.
"It was a headwind and it was like a slow motion sprint, and I was lucky to get it on the line," Henderson said.
"It's beautiful to win here and to win such a beautiful race is real honor." Boom won the race prologue Sunday and finished in the main pack with the same time as Henderson and retained the yellow jersey, 5 seconds ahead of German veteran Jens Voigt. British rider David Millar is in third place, 13 seconds back.
Two-time Tour de France winner Alberto Contador fell behind over the last 15 kilometers and moved down to eighth place in the standings, 25 seconds behind Boom.
Contador also crashed three kilometers from the finish line but didn't appear injured.
Romain Feillu of France launched the first attack early in the stage and was followed by Dutchman Albert Timmer. With the help of a strong tailwind, they set a high tempo at front and rode alone for 146 kilometers before being caught about 50 kilometers from the finish line.
Philippe Gilbert, last year's Tour of Lombardy winner, and Dutchman Tom Veelers tried their luck with 41 kilometers to go and quickly built a one-minute lead while American rider Levi Leipheimer was held up by a crash at the back of the peloton.
About 30 riders were caught in the pileup but were able to get back on their bikes.
On very narrow roads, Contador's Astana team and riders from the Rabobank squad chased the two breakaway companions, who were reined in by the peloton with 16 kilometers to go.
Alejandro Valverde and three other Caisse d'Epargne riders, including defending champion Luis Leon Sanchez, attacked at the front of the peloton a few minutes later, using the windy conditions to their advantage in a tactic known as "bordure," which can help breakaway groups gain time on the main pack.
Contador was caught off-guard while Boom reacted quickly and joined the group of breakaway riders along with overall Valverde and Sanchez.
Contador crossed the finish line 17 seconds behind the stage winner.
The Paris-Nice race ends on Sunday. Tuesday's second stage will take the riders from Contres to Limoges on a 201K trek featuring three third-category climbs.