President Donald Trump, in his biggest foreign policy decision since taking office in January, ordered the strikes after concluding that Syria waged a nerve gas attack in rebel-held territory that killed 87 people, many of them children.
Russia, which has advisers on the ground aiding Syrian President Bashar al Assad, warned the US strike could have serious consequences. Syria denies involvement.
White House warns Syria on chemical, barrel bomb use
"It will not spiral out of control," Mattis told reporters at the Pentagon.
"I'm confident the Russians will act in their own best interest and there is nothing in their best interest to say they want this situation to go out of control."
Mattis has repeatedly warned that the US military remained ready to act again should Assad use chemical weapons, saying on Tuesday that Assad would "pay a very, very stiff price."
At the same time, he acknowledged that Trump had only authorized the single attack, meaning the US military would not automatically have the authority to strike again should Washington determine another case of chemical weapons use.
Mattis also sought to downplay concerns about Pentagon mission creep, saying the US military's focus in Syria was still fighting Islamic State militants, not becoming entangled in Syria's messy civil war between Assad and his opponents.
"The rest of the campaign stays on track exactly as it was before Assad's violation," Mattis said.
US CAN'T PROVE RUSSIA ROLE
The incident has chilled US relations with Moscow after a presidential campaign during which Trump frequently called for an alliance with Russia to fight Islamic State militants in Syria and Iraq.
It has also led the Trump administration to harden its attitude against Assad weeks after top US officials said they were more concerned with defeating Islamic State militants than getting Assad out of power.
"I don't see a peaceful, stable Syria in the future that has Assad in charge," White House spokesman Sean Spicer said on Tuesday. "I don't see a future Syria that has (Assad) as the leader of that government."
US Secretary of State Rex Tillerson denounced Russian support for Assad as he prepared to fly to Moscow on Tuesday.
"It is clear to us the reign of the Assad family is coming to an end," Tillerson told reporters in Italy.
US intelligence indicates that Syrian Su-22 aircraft taking off from Shayrat airfield delivered the nerve agent sarin, according to a White House report given to reporters.
Mattis said there was no doubt that Damascus was responsible.
UK defense minister: Russia responsible by proxy for Syria chemical deaths
Although some US officials have strongly hinted they suspect Russia, which has a presence at Shayrat, may have known something about the planned attack, none have conclusively linked Moscow to the incident itself.
Mattis suggested the United States did not have firm evidence that Russia had foreknowledge or was complicit in the chemical attack.
"It was very clear that the Assad regime planned it, orchestrated it and executed it and beyond that we can't say right now. We know what I just told you, we don't know anything beyond that," Mattis said, when asked whether Russia had a role.
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