Bhagirath, grandfather of Isa Khan, belonged to the Kshatriya Rajput community. He came to Bengal from Ayodhya and took the job of Dewan under the Sultan of Bengal Ghiyasuddin Mahmud Shah (reigned 1533–1538). His son Kalidas Gazdani inherited the post after his death. Later, Kalidas converted to Islam and took the Muslim name Sulaiman Khan. Sulaiman married Sultan's daughter Syeda Momena Khatun and got the Zamindari of Sarail (present-day Sarail Upazila, Brahmanbaria, Bangladesh) in Bhati region. Their son, Isa Khan, was born in Sarail.
Following the death of Sultan Ghiyasuddin, Sulaiman declared himself as the legal successor and revolted against the newly established Afghan rule. Later he was killed in a battle.
According to Abul Fazl, a 16th-century historian and the author of Akbarnama:
With the help of Taj Khan, a Karrani ruler during 1564-1566, Isa obtained an estate in Sonargaon and Maheswardi Pargana in 1564 as a vassal of Karrani dynasty of Bengal. He gradually increased his power. In 1573 he helped Daud Khan Karrani in his expedition to Chittagong against Udaya Manikya, the king of Tripura. He also helped Kala Pahar, Daud Khan's General, in driving out the Mughal's Navy from the vicinity of Sonargaon in 1575. Is
Khan died of natural causes in September 1599.
On 12 February 1909, a farmer unearthed seven cannons in Monwarbagh. The cannons were partly made of brass. They had labels "Isa Khan" and "1002" (Hijri 1002 year is 1593 CE in Gregorian Calendar). These cannons were made from the era of Sher Shah Suri who ruled Bengal before the Bara Bhuiyans while at least three cannons which carved with Isa Khan labels were made during Bara Bhuiyans independent era from Mughals.
Bangladesh Navy has named a base, BNS Issa Khan in his honor. The base, BNS Isa Khan, was the first Bangladesh Navy base to receive the national standard in 1974.