Biden wanted to avoid a regional war. Now he’s got one.

On Saturday, he got the escalation he sought to avoid. Iran fired more than 300 drones and missiles, marking the first time that Tehran has directly attacked Israel.

With that barrage, Iran has set aside the veneer of deniability it has long tried to exploit by supporting regional proxies. The direct attack forces Israel to confront the question of how to respond militarily and presents the Biden administration with the challenge of finding a way to avert the larger regional conflict it has long feared.

For now, the Biden administration is hoping that international political pressure on Iran and quiet suasion with Israel, which has become increasingly dependent on U.S.-led air and missile defense protection for its security, will dial down tensions.

Yet even if escalation can be avoided in the coming hours and days, the U.S. and its foremost Middle East ally will have to grapple with a volatile region that increasingly requires American political and military involvement despite the White House’s early hopes to shift its attention to Asia.

“The Middle East has changed. The red line that Israel and Iran would not directly attack the other country is now erased," said Norman Roule, who served as a top U.S. intelligence official on Iran. “Each country will now claim they can use this option in response to security threats, although any future attacks may not be on this scale."

For decades, Iran has primarily worked through a network of Middle East proxies in Iraq, Syria, Lebanon and Yemen as it sought to avoid a full-scale conventional conflict with the U.S. and Israel.

Those militias were deadly. During the U.S. war in Iraq, hundreds of U.S. troops were killed and wounded by explosively formed penetrators—a type of roadside bombs that Iran provided to Shia militias. Iran also trained and equipped Hamas fighters, though the U.S. has concluded that Tehran didn’t orchestrate Hamas’s Oct. 7 attack on Israel.

At times, Iran turned to its missiles and drones to lash out at its foes. In September 2019, Iranian drones and cruise missiles were used to strike oil-processing facilities at Abqaiq, Saudi Arabia, U.S. and regional officials said, after tensions grew between Tehran and Riyadh.

Iran also fired ballistic missiles at U.S. forces at the Al Asad air base in Iraq after then President Donald Trump ordered a drone strike that killed Qassem Soleimani, the head of the Islamic Revolutionary Guard Corps’ Quds Force, near the Baghdad airport in January 2020. Timely intelligence enabled the U.S. to shift personnel out of harm’s way before Iran’s missiles struck, though more than 100 Americans suffered concussions and brain injuries.

Yet those missile barrages were generally the exception to Iran’s strategy of strengthening the military capabilities of regional allies such as Hezbollah and Hamas, which regularly carried out attacks against Israel, while avoiding strikes that had a clear Iranian return address.

In a statement Saturday night, Iran made clear that its barrage wasn’t intended as the opening phase of a new conventional war but was punishment for the April 1 Israeli airstrike against top Iranian paramilitary commanders in Damascus earlier this month.

“The matter can be deemed concluded," Iran’s Mission to the United Nations said in a statement. “However, should the Israeli regime make another mistake, Iran’s response will be considerably more severe. It is a conflict between Iran and the rogue Israeli regime, from which the U.S. MUST STAY AWAY!"

With that notice, Iran was offering to end the current round of open hostilities between Israel and Tehran on its terms and putting the ball in Israel’s court.

Biden’s counsel to Israeli Prime Minister Benjamin Netanyahu in a Saturday night call was that this was a time for careful reflection. Israel, Biden argued, had come out ahead: Israel had killed Islamic Revolutionary Guard leaders in its Damascus strike while Iran’s missile and drone attacks had been largely neutralized.

“The president was very clear that we’re going to help defend Israel, and he made very clear to the prime minister last night that we do have to think carefully and strategically about, you know, risk of escalation," a senior Biden administration official told reporters Sunday.

Israeli Defense Minister Yoav Gallant told U.S. Defense Secretary Lloyd Austin last week that a direct Iranian attack on Israel “will require an appropriate Israeli response against Iran," according to a statement from Gallant’s office.

But while Israel didn’t consult the U.S. on its Damascus strike, the American and European role in helping Israel fend off Iran’s drone and missile attacks may have given Washington additional leverage in influencing the Israelis’ calculations. Whatever military response Israel may opt for against Iran, Biden administration officials made clear the U.S. wouldn’t be part of it.

Frank McKenzie, the retired general who led the U.S. Central Command when it carried out the strike that killed Soleimani, said Iran has suffered a military setback by failing to damage Israel with its drone and missile attack and that Israel should take that into account in weighing a military response.

“The Iranians are weaker today than they were yesterday," McKenzie said. “Whatever they say, everybody knows this attack failed. And that’s good news for Israel."

But if Israel does decide to respond, it should do so quickly, and with a focused strategy. “And then walk away from a famous victory," he said.

Write to Michael R. Gordon at michael.gordon@wsj.com