The massive strike – the first direct US action against President Bashar al-Assad's government and Trump's biggest military decision since taking office – marked a dramatic escalation in American involvement in Syria's six-year war, agencies reported.
It followed days after a suspected gas attack in the terrorist-held town of Khan Sheikhun.
US officials said 59 Tomahawk cruise missiles were fired from Navy ships in the Mediterranean at the Shayrat airfield at 3:40 a.m. (0040 GMT), hitting the base from where Washington believes Tuesday's “gas attack” was launched.
The strike targeted radars, aircraft, air defense systems and other logistical components at the base south of Homs in central Syria.
In a statement read on state television, the Syrian Army said the strike had caused extensive damage.
Nine planes as well as munitions and fuel depots were destroyed in the strike but the runway was intact, Russian channel Rossiya24 reported from the scene.
The Syrian government denounced the strike as a "flagrant aggression" and state news agency SANA said nine civilians including four children had been killed in villages near the base.
The office of President Assad called the strike "reckless" and "irresponsible."
The attack was hailed by the Syrian armed opposition and supported by US allies including Britain, France, Germany, Israel, Japan, Saudi Arabia and Turkey.
But it was denounced by Iran and Russia, with Moscow warning that it would inflict "considerable damage" on Russia-US ties and halting an agreement with Washington aimed at avoiding clashes in Syrian airspace.
A spokesman for the Russian president said Vladimir Putin regarded the US action as "aggression against a sovereign nation" on a "made-up pretext.”
Iranian Foreign Minister Mohammad Javad Zarif censured the attack, saying the United States is fighting on the same side as Al-Qaeda and Daesh terrorist groups.
“As the only recent victim of mass use of chemical weapons (by [former Iraqi dictator] Saddam [Hossein] in the '80s, Iran condemns use of all WMD (weapons of mass destruction) by anyone against anyone,” Zarif said in a post on his Twitter account on Friday.
He emphasized that Washington helped Saddam in its chemical weapons attack against Iran, but the US has twice in the current millennium used "bogus" chemical weapons allegations to use military force, including in the 2003 invasion of Iraq and the current strikes against Syria.
The top Iranian diplomat added that it is high time to stop “hype and cover-ups”.
Russia stood by Damascus this week, insisting that the chemical weapons that caused the deaths in Khan Sheikhun had been stockpiled by terrorists and possibly released by a conventional strike.
"We call upon the UN Security Council to hold an extraordinary meeting to discuss the situation," the Russian Foreign Ministry said in a statement, calling the strike "thoughtless."
US officials said Russia's military in Syria was informed of the strike beforehand in order to avoid casualties that could prompt a broader crisis.
In 2013, Trump had urged then-president Barack Obama not to intervene against Assad.