A suspect has been taken into custody and the area secured, police said.
The White House was placed into lockdown, while US President Donald Trump is away in Florida.
Mr Trump posted on his Truth Social platform to say the two guardsmen had been “critically wounded”, adding that the “animal” that shot them “is also severely wounded, but regardless, will pay a very steep price”.
Washington DC shooting latest updates
US homeland security secretary Kristi Noem said: “Please join me in praying for the two National Guardsmen who were just shot moments ago in Washington DC.”
The Joint DC Task Force confirmed it was responding to an incident in the vicinity of the White House.
The DC Police Department posted on X: “Critical Incident: MPD is on the scene of a shooting at 17th and I Street, NW. Please avoid the area.”
In an update, they said: “The scene is secured. One suspect is in custody.”
White House press secretary Karoline Leavitt said: “The White House is aware and actively monitoring this tragic situation.
“The president has been briefed.”
Mr Trump was at his resort in Palm Beach ahead of the Thanksgiving holiday, while US vice president JD Vance was in Kentucky.
Flights arriving at Ronald Reagan Washington National Airport were halted due to its proximity to the scene of the shooting, a Federal Aviation Administration official told NBC News, Sky News’s US partner.
Hundreds of National Guard members have been patrolling the nation’s capital after Mr Trump issued an emergency order in August, which federalised the local police force and sent in the guard from eight states and the District of Columbia.
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