The war games involve 12,000 US military personnel and 230 aircraft - including US F-22 Raptor stealth fighter jets - and will run until Thursday. South Korean F-15K, KF-16, and F-5 fighters will also take part.
Named Vigilant Ace, the air manoeuvres will simulate strikes on "mock North Korean nuclear and missile targets and transporter erector launchers that move the North's missiles", the South Korean Air Force was quoted by Yonhap news agency as saying on Sunday.
The exercises come after last week's test-launch by North Korea of its most powerful intercontinental ballistic missile (ICBM) yet, though the US-South Korea drills had already been planned.
The Hwasong-15 ICBM could theoretically travel about 13,000km - far enough to hit anywhere in the mainland US.
While the Monday-Thursday exercise is a biannual training event, it is unusual for advanced stealth aircraft such as the F-22 and F-35 to participate, Yonhap reported.
North Korea reacted angrily on Sunday to the air manoeuvres, accusing the US and South Korea of a "grave military provocation" that will "push the already acute situation on the Korean Peninsula to the brink of nuclear war.
"What matters is the fact that the drill simulating an actual war is to be staged at a time when insane President Trump is running wild," a commentary carried by the official Korean Central News Agency said.
"The situation clearly proves that the US and the South Korean puppet war maniacs are just aggressors and provocateurs breaking peace and stability on the Korean Peninsula."
The war games follow reports on Saturday of the establishment by South Korea's military of a "decapitation unit" tasked with neutralising the North's leadership - including Kim Jong-un - and destroying nuclear and missile facilities if war breaks out.
The unit, comprising 1,000 special forces troops, is modelled after the US Army Rangers, Delta Force, SEAL Team Six, and Green Berets, according to a report by the Korean Times newspaper.
The unit was originally to be launched in 2019, but the military expedited the move because North Korea "continues to raise regional tensions with its ballistic missile launches and nuclear experiments", the report said.
On Sunday, US National Security Adviser HR McMaster said President Donald Trump was prepared to "take care" of the North's weapons programmes - but he didn't specify how.
"If necessary, the president and the United States will have to take care of it because he has said he's not going to allow this murderous, rogue regime to threaten the United States with the most destructive weapons on the planet," McMaster told Fox News on Sunday.