Mangudadatu was born on August 15, 1968, to Pua Mangudadatu, a politician that was president of the "Magnificent 7", a group of influential politicians in the province at the time. An uncle is Pax Mangudadatu, incumbent representative of the 1st district of Sultan Kudarat in Tacurong City.
Seeking to escape his political dynasty, Mangudadatu went to University in order to be a doctor. It was there that Mangudadatu met his wife Genalyn, from the Ilongga clan, while they were both students in Davao City, Mindanao. They married on November 11, 1991. Starting a family after getting married cut his medical studies short but even after having many children he earned his Political Science degree from the University of Mindanao in Davao City.
Mangudadatu visited the then governor of Maguindanao province, Zacaria Candao, to obtain approval for a new business venture. Instead, Candao, who was also Mangudadatu's godfather, talked him into running for office. He was elected and became a provincial board member. He went on to become Mayor of Buluan and after he reached his term limit became Vice Mayor. In 2009 he decided to challenge the Ampatuan clan's heir apparent in the election for governor of Maguindanao province.
The Maguindanao massacre occurred on the morning of November 23, 2009, in the town of Ampatuan in Maguindanao province, on the island of Mindanao in the Philippines. The victims were about to file a certificate of candidacy for Esmael Mangudadatu. Mangudadatu was challenging Datu Unsay mayor Andal Ampatuan Jr., son of the incumbent Maguindanao governor Andal Ampatuan Sr., in the forthcoming Maguindanao gubernatorial election, part of the national elections in 2010. The 57 people killed included Mangudadatu's wife, two of his sisters, and a cousin, in addition to numerous journalists, lawyers, aides, and motorists who were witnesses or were mistakenly identified as part of the convoy. Mangudadatu told reporters that his wife was able to call her husband just before she was killed, "She said... they had been stopped by 100 uniformed armed men... then her line got cut off,"
The man thought responsible Andal Ampatuan Jr. denies that he was responsible and instead blames the MILF an armed Islamic group that operates in the Southern Philippines. MILF released a statement denying that it was responsible.
Four days after the massacre, Mangudadatu traveled along the same road where the attack had occurred to successfully file his candidacy in the election. He ran under the banner of the Lakas Kampi CMD party. In the Lakas Kampi CMD party, Mangudadatu replaced his rivals from the Ampatuan clan who were the perpetrators of the Maguindanao massacre.
On February 11, 2010, Tamano Kamendan approached Mangudadatu and his entourage at the Gaisano South Citimall in Davao City. An altercation took place and Kamendan was killed by Esmael Mangudadatu's bodyguard. Mangudadatu released a statement that Kamendan was an associate of the Ampatuan clan and that he was trying to kidnap his children. Kamendan's wife denies the Ampatuan connection and has stated in an affidavit that her husband was just shopping when Mangudadatu ordered his men to shoot him. On February 14, 2010, Mangudadatu and his bodyguard were charged with murder.
Mangudadatu's convoy on August 15, 2011, was hit by a car bomb that exploded along a highway in Tacurong city, Sultan Kudarat. Two people were killed, including a Maguindanao board member, while six others were wounded. The bomb exploded while Mangudadatu's convoy was cruising along the highway in Tacurong. The governor and his followers were heading to a restaurant to celebrate his birthday.
The bomb, placed inside an old and white Kia vehicle that was parked at the side of the road fronting the Cherubim Methodist Learning Center in Alunan Highway, exploded when a Toyota Fortuner, where the provincial board member was on board, passed near it. Mangudadatu was unhurt in the bombing because his vehicle was bullet-proof.