Meanwhile, on the paternal side, he was the nephew of Juan de Dios Amador, governor of Cartagena during Morillo's siege, and Martín Amador, executed by the Spaniards in 1816.

Manuel Amador was born to José María Amador and Mercedes Guerrero and Córdoba. He studied medicine at the University of Cartagena and emigrated to Panama in 1855. That year the Trans-Isthmic Railroad opened, bringing relative prosperity to this department, which became a crucial juncture for North American people and merchandise during the so-called 'gold rush'. Amador was hired as a doctor for the Railway Company, the company that years later would push for the separation of the Isthmus from Colombia. His marriage to María de la Ossa tied him to the prosperous and powerful business families of the isthmus. 

Around the 1860s, Amador appeared on the scene of local politics within the Conservative Party, and became recognized upon being appointed to important public titles: Congressional representative for the province of Veraguas, First Designate of the Sovereign State of Panama in 1866, President of Panama in 1867, although he could not hold office, Acting Civil and Military Chief in 1886 and assistant to the governor Victor Salazar during the Thousand Day War, who proposed that he be a member of the Senate from 1902 to 1903, a position that was taken from him by Vice President Marroquín, which, according to Lemaitre, served as one of his personal motives to encourage the "separation".

His conservative activism, family ties and close relationship with North American interests may explain why he played such a key role in the crucial moment when the government of Theodore Roosevelt decided to take over Panama to build the Panama Canal, after the Colombian Congress had rejected the Herrán- Hay Treaty on August 12, 1903. Nevertheless, according to Ovidio Díaz, "at first glance, Dr. Manuel Amador Guerrero seemed a quite unlikely candidate to lead a revolution."