During the rule of the Devagiri Yadavs (1248 - 1318) and the Tughlaqs (1318 - 1347), Karnala served as the capital of the north Konkan districts of the respective empires. Later, the city was taken over by the Gujarat Sultanate, who then lost Karnala to the Nizam Shah of Ahmednagar in 1540. The Gujarat sultans then sought the help of the commanding officer of the Portuguese at Bassein to win it back, and recaptured it.
Later, a battle took place between the Nizam Shah and the Portuguese, in which the latter won. Karnala thus, came under the rule of the Portuguese; however, the fort of Karnala was given to the Nizam Shah by the Portuguese viceroy to nurture their friendship.
In 1819, the British East India Company established its rule in the region. Karnala was considered strategically important as it commanded the trade route between Bhor Ghat and the rivers of Panvel and Apta. The region was declared as a bird sanctuary by the Maharashtra Government in 1968.