BEIRUT—Dozens of State Department officials this week protested against U.S. policy in Syria, signing an internal document that calls for targeted military strikes against the Damascus government and urging regime change as the only way to defeat Islamic State.

The “dissent channel cable” was signed by 51 State Department officers involved with advising on Syria policy in various capacities, according to an official familiar with the document. The Wall Street Journal reviewed a copy of the cable, which repeatedly calls for “targeted military strikes” against the Syrian government in light of the near-collapse of the ceasefire brokered earlier this year.

The views expressed by the U.S. officials in the cable amount to a scalding internal critique of a longstanding U.S. policy against taking sides in the Syrian war, a policy that has survived even though the regime of President Bashar al-Assad has been repeatedly accused of violating ceasefire agreements and Russian-backed forces have attacked U.S.-trained rebels.

The State Department acknowledged the existence of the cable, which is a formal, confidential diplomatic communication, but wouldn’t comment on its contents until top officials had a chance to review it.

Obama administration officials have expressed concern that attacking the Assad regime could lead to a direct conflict with Russia and Iran.

John Kirby, a State Department spokesman, said the “Dissent Channel” is an official forum that allows employees to express opposing views. State Department regulations expressly prohibit retaliation against any employee who uses the channel to voice disagreement.

The complaint filed by the State Department officials wasn’t unusual, current and former U.S. officials said, but the number of diplomats actively opposing a major White House position was.

“It’s embarrassing for the administration to have so many rank-and-file members break on Syria,” said a former State Department official who worked on Middle East policy.

These officials said dissent on Syria policy has been almost a constant since civil war broke out there in 2011. But much of the debate was contained to the top levels of the Obama administration. The recent letter marked a move by the heart of the bureaucracy, which is largely apolitical, to break from the White House.

The internal cable may be an attempt to shape the foreign policy outlook of the next administration, the official familiar with the document said. President Barack Obama has balked at taking military action against Mr. Assad, while Democratic presidential hopeful Hillary Clinton has promised a more hawkish stance toward the Syrian leader. Republican candidate Donald Trump has said he would hit Islamic State hard but has also said he would be prepared to work with Russia in Syria.

The cable warns that the U.S. is losing prospective allies among Syria’s majority Sunni population in its fight against the Sunni extremist group Islamic State while the regime “continues to bomb and starve” them. Mr. Assad and his inner circle are Alawite, a small Shiite-linked Muslim sect and a minority in Syria. In Syria’s multisided war, the regime, Islamic State and an array of opposition rebel groups are all battling each other.

“Failure to stem Assad’s flagrant abuses will only bolster the ideological appeal of groups such as Daesh, even as they endure tactical setbacks on the battlefield,” the cable reads, using an Arabic acronym for Islamic State.

Although Islamic State is losing ground to multiple, U.S.-backed offensives in Syria, Iraq and Libya, Western diplomats say they worry the group has embedded itself so deeply in the population that it will be a major influence for years to come, eventually going underground as its quasi-army is defeated.

Moscow on Thursday called for a long-term ceasefire in the northern city of Aleppo, after helping regime forces encircle the city for weeks. The Russian military is providing air support to the Syrian army and its allies on the ground such as Iran and Hezbollah, the Lebanese Shiite political and militia group.

Both opposition rebels and the Damascus government have violated the cease fire, which took effect on Feb. 27. But the death toll exacted by pro-regime forces has been higher, partly because they have been using barrel bombs dropped by helicopters and been aided by the Russian air force, monitoring groups say. The rebels largely use cruder, homemade weapons such as improvised mortar shells.

The cable asserts Mr. Assad and Russia haven’t taken past cease-fires and “consequential negotiations” seriously and suggests adopting a more muscular military posture to secure a transitional government in Damascus.

It calls for the U.S. to change course and create a more robust partnership with moderate rebel forces to fight against both Islamic State and Mr. Assad’s government. Many Syrian Arab rebels have been reluctant to join the U.S.-led coalition because of its singular focus on Islamic State and not on the regime.

Such a force would shift “the tide of the conflict against the regime [to] increase the chances for peace by sending a clear signal to the regime and its backers that there will be no military solution to the conflict.”

Separate CIA and Pentagon programs to train and equip Syrian Arab rebels have failed to produce a large ground force to fight Islamic State. Russian airstrikes last year also targeted and drove back the CIA’s closest rebel allies, which the agency had supplied with advanced antitank missiles to help them fight Islamic State.

A lack of Arab fighters has slowed the military advance of the U.S.-backed and Kurdish-led Syrian Democratic Forces, or SDF, which is currently on the offensive and taking territory from Islamic State.

The advance of the SDF was recently halted until more Arab rebels were rolled into the force, Western diplomats say, after the opposition protested the ethnic composition of the group, as did some of its regional allies.

The SDF is currently surrounding the town of Manbij in northern Aleppo province, a major administrative and agricultural center for the extremists. If taken, Manbij would be the biggest Syrian population center reclaimed from Islamic State, helping to pave the way for the U.S.-led coalition to move on the group’s self-proclaimed Syrian capital of Raqqa.

The Russian-led force is also pushing toward Raqqa from the south, making the march on the Islamic State stronghold a strategic and symbolic competition between the rival coalitions. Islamic State is also being rolled back in Iraq, where U.S.-allied government forces have retaken major cities and are advancing in Fallujah, the first city the extremists fully occupied back in 2014.

The cable also echoes the growing impatience among U.S. Gulf allies with the lack of military intervention targeted at the Damascus government to force Mr. Assad to resign and make way for a transitional government. Peace talks between Syria’s government and opposition collapsed in April over Mr. Assad’s fate, with the regime insisting he should stay in power, while the negotiated cease-fire continued to disintegrate.

Saudi Arabia and the United Arab Emirates have pressed the U.S. to provide more sophisticated weapons to rebels. But Washington has resisted.

Allowing the regime to commit large-scale human rights abuses “against the Syrian people undermines both morally and materially, the unity of the anti-Daesh coalition,” the cable reads.

Write to Maria Abi-Habib at maria.habib@wsj.com