The organisation, which goes by its French initials MSF, said the hospital attacked Saturday morning was one it supports.
"This bombing shows all the signs of a double-tap, where one area is bombed and then a second bombing hits the paramedic response teams or the nearest hospital providing care," Brice de le Vingne, MSF director of operations, said in a statement.
"This double-tap tactic shows a level of calculated destruction that can scarcely be imagined," he added.
MSF said the first barrel bomb was dropped from a helicopter on a populated area of Al-Zafarana town near the city of Homs on Saturday at 9:40 am (0740 GMT), killing a man and a young girl and wounding 16 people.
Soon after the patients were all admitted to the Al-Zafarana hospital, three more barrel bombs landed nearby, killing one bystander and wounding 31 patients under treatment and medical staff.
Parts of the hospital were destroyed and the kidney dialysis unit was heavily damaged, MSF said.
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The most critically wounded patients were transferred to three nearby hospitals. Five of them died en route.
In total, seven people died and 47 were wounded, including 23 women and children under the age of 15, MSF said.
The organisation said it was offering support to repair or relocate the hospital facility, and was preparing to send essential medical supplies to help the hospital team continue operating.
"This makeshift hospital was providing a lifeline of care to around 40,000 people," de le Vingne said.
"It is already a tragedy that seven people, including a small girl, have been killed, but if the hospital has to close down or reduce activities, that is a double tragedy for the people living under the permanent threat of war, with nowhere else to turn for medical assistance," he added.
MSF, which operates six medical facilities in northern Syria and directly supports more than 150 health posts and field hospitals across the country, reiterated its call for all parties in the Syrian conflict to avoid attacking civilians and civilian infrastructure, including hospitals and ambulances.
"The multiplication of these atrocious attacks, with overwhelmingly high numbers of civilians, including women, children and medical staff, wounded and killed, must cease," it said.