Attacks on the rebel-held capital Sanaa as well as Saada, Al-Bayda and Radaa killed at least 31 people and wounded 101, "most of whom were children and women", Huthi health ministry spokesperson Anis al-Asbahi said.
US President Donald Trump said he had ordered Saturday night's strikes and threatened more if the rebels kept up their attacks on Red Sea and Gulf of Aden shipping.
The rebels have carried out no attacks in the waterways since January 19, when a ceasefire began in the Gaza Strip, but on Tuesday said they would resume attacks on Israeli shipping.
US National Security Advisor Michael Waltz told ABC News the strikes "targeted multiple Huthi leaders and took them out."
He told Fox News: "We just hit them with overwhelming force and put Iran on notice that enough is enough."
The Huthis, who have fought for years in their country, vowed a response.
Witnesses to the bombing said on Sunday they were taken aback by its intensity.
Footage on Huthi media showed children, including a dazed girl with blackened legs wrapped in bandages, and a woman being treated in hospital.
- 'Terrified' -
One father of two, who gave his name as Ahmed, told AFP his "house shook, the windows shattered, and my family and I were terrified".
"I've been living in Sanaa for 10 years, hearing shelling throughout the war. By God, I've never experienced anything like this before," he said.
Trump, posting on social media, vowed to "use overwhelming lethal force" to end the Huthi attacks, which the rebels say are in solidarity with Palestinians during the Gaza war.
"To all Houthi terrorists, YOUR TIME IS UP, AND YOUR ATTACKS MUST STOP, STARTING TODAY. IF THEY DON'T, HELL WILL RAIN DOWN UPON YOU LIKE NOTHING YOU HAVE EVER SEEN BEFORE!" he said.
Trump also issued a stern warning to Tehran.
"To Iran: Support for the Houthi terrorists must end IMMEDIATELY!" he said.
The Huthis, who had long complained of marginalisation, seized Sanaa in September 2014, forcing the government to flee south and leaving the rebels controlling large parts of the country.
A Saudi-led coalition in March 2015 began a military campaign against the Huthis that the Yemen Data Project, an independent tracker, said involved more than 25,000 air raids.
Iran's Foreign Minister Abbas Araghchi condemned the deaths in the US strikes and said Washington had "no authority" to dictate Tehran's foreign policy.
US Central Command, which posted videos of warplanes taking off and a bomb demolishing a compound, said "precision strikes" were launched to "defend American interests, deter enemies, and restore freedom of navigation".
- 'Fully prepared' -
The Huthis' political bureau said its "forces are fully prepared to confront escalation with escalation".
They have launched scores of drone and missile attacks on ships in the two key waterways.
Pentagon spokesman Sean Parnell said the Huthis had "attacked US warships 174 times and commercial vessels 145 times since 2023".
The Yemen Conflict Observatory database set up by ACLED, a non-profit monitor, shows 136 Huthi attacks against warships, commercial vessels, Israeli and other targets since October 19, 2023.
The campaign put a major strain on the vital trade route, which normally carries about 12 percent of world shipping traffic, forcing many companies to take a costly detour around southern Africa.
The Palestinian group Hamas, which has praised Huthi support, branded the US strikes "a stark violation of international law and an assault on the country's sovereignty and stability".
Iran denounced them as a "gross violation of the principles of the UN Charter".
The head of Iran's Revolutionary Guards, Hossein Salami, said: "Iran will not wage war, but if anyone threatens, it will give appropriate, decisive and conclusive responses."
- 'Political dialogue' -
The United States had already launched several rounds of strikes on Huthi targets.
Israel has also struck Yemen, most recently in December, after Huthi missile fire towards Israeli territory.
Trump's administration this month reclassified the Huthis as a "foreign terrorist organisation", banning any US interaction with the group.
US Secretary of State Marco Rubio also spoke to his Russian counterpart Sergei Lavrov. Moscow is close to Tehran.
"Continued Huthi attacks on US military and commercial shipping vessels in the Red Sea will not be tolerated," Rubio told Lavrov, according to the State Department.
Russia's foreign ministry said "Lavrov stressed the need for an immediate cessation of the use of force and the importance for all sides to engage in political dialogue... (to) prevent further bloodshed".
Fighting in Yemen's own war has largely been on hold since a 2022 ceasefire, but the promised peace process has stalled in the face of the Huthi attacks on Israel and Israel-linked shipping.
The war killed hundreds of thousands either directly or indirectly through causes such as disease. The country plunged into one of the world's worst humanitarian crises.
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