In a statement, the U.S. Africa Command says it conducted three "precision strikes" against al-Shabab at around 2:15 am in an area 260 kilometers south of the capital, Mogadishu.
The mayor of the town of Barawe, Aden Omar Madobe says the airstrike occurred in Kunyo Barrow village and hit an al-Shabab militia site.
There was no immediate word on the identity of those killed. Previous U.S. airstrikes in Somalia have killed many al-Shabab leaders, including the group's emir, Ahmed Godane, in 2014.
Wednesday's airstrikes were conducted in coordination with the Federal Government of Somalia, AFRICOM said.
"The U.S. conducted this operation within the parameters of the authorities granted by the president in March which allows U.S. forces to conduct lethal action against al-Shabab within a geographically-defined area in support of partner forces in Somalia," the statement read.
In a follow up note, AFRICOM says its assessment is that "there were no civilians anywhere near the site.'
Madobe told VOA Somali that Al-Shabab fighters disconnected the communications network of the area after the attack.
"What we know of them is that they disconnect communication whenever anti-peace elements suffer many casualties," he said.
It's the third U.S. airstrike this month alone in and around Kunyo Barrow, in the Middle Jubba region. The fourth attack took place on September 5 in Dodale, in the Bay region, where the U.S. says three militants were killed.
Wednesday's U.S. airstrike comes against the backdrop of increased Al-Shabab attacks against Somali government this month, with at least seven deadly attacks so far.
One of three Somali journalists wounded in a suicide bombing Sunday in Beledweyne succumbed to his injuries on Wednesday.
Abdullahi Osman Moallim, 24, who was a reporter for a local TV and radio station, suffered head injuries when the bomber detonated an explosive vest in a crowded teashop.
The United States sent condolences for the death of the journalist and condemned Al-Shabab's "indiscriminate attacks.'
"We salute and encourage Somali journalists to continue their work despite the daily struggles and risks, in defense of the inalienable right of freedom of expression on behalf of the Somali people," read a statement issued by the United States mission to Somalia.
Al-Shabaab has been trying since 2006 to overthrow the government and impose a strict form of Sharia in Somalia.