Militants from Al-Qaeda-linked Ansar al-Sharia stormed the seaside base after a suicide bomber rammed a car into the entrance, a military official said.
The militants, who were dressed in special forces uniforms and drew up in four military vehicles, then took much of the garrison hostage, the official said.
The commander of the army's second military region, General Muhsen Hasan, thought initially to have been captured, was outside the building at the time of the attack, another official said.
Army reinforcements have been deployed to the area and have engaged the militants, a third official, warning that militants would "pay a heavy price" for the spectacular attack.
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"Army troops and security forces have cordoned off the entire area," he said.
Mukalla is capital of Yemen's southeastern province of Hadramawt and a major port city.
It is the second major assault on the Yemeni army by Al-Qaeda in 10 days.
On September 20, suspected Al-Qaeda fighters killed at least 56 soldiers and police in coordinated dawn attacks in Shabwa province further west.
Washington regards Al-Qaeda in the Arabian Peninsula as the global jihadist network's most dangerous affiliate and has stepped up its drone strikes against the group in recent weeks.