The Panamanian isthmus was the scene of Christian evangelism very early in colonial history. The Diocese of Santa María la Antigua del Darién, founded in 1513, is the oldest in the mainland of the American continent. Its headquarters were moved to Panama City a decade later, and the historic headquarters today are located in Colombian territory. However, the 60 missions that existed on the Isthmus of Panama during the colonial period encountered strong resistance from local populations, particularly in Guna and Mosquito. Fewer than 20 of these missions remained at the time of independence, decimated by massacres and epidemics.

The first Protestant presence in Central America appeared between 1698 and 1700, in a short-lived Scottish colony called New Caledonia on the Caribbean coast of the Darien. In the nineteenth century, Anglican, Baptist and Methodist missions settled in the country, targeting the Anglophone population of the Antilles who had come for the construction of the railroad (1850–5) and the canal (1881–1914). Only in 1928, with the installation of the first Evangelical denomination, the Church of the Foursquare Gospel, did the Protestant presence in Panama begin to address itself to the Hispanic population.

The Christian proportion decreased from 98.8% of the Panamanian population in 1911 to 81.2% in 2018. In addition, it was pluralised: while 90.7% of the Christian population was Catholic in 1911, they represented only 59.85% in 2018 (figures from the census of 2011 and Latinobarómetro). The non-Catholic Christian population, in turn, tends to fragmentation, although the Church of the Foursquare Gospel, the Seventh-day Adventist Church and the Assemblies of God account for roughly half of the total.

Several places of pilgrimage and devotion exist within Panamanian Christianity. Without a doubt, the most interesting one, due to its syncretic character, is the Black Christ of Portobelo, on the Caribbean coast of the country, which inspired the song ‘El Nazareno’ by the Puerto Rican singer Ismael Rivera. The Panamanian religious leadership was nationalised during the twentieth century. The Bishop of Panama City had been Panamanian only three times between 1513 and 1964. However, since 1964, the archbishops have consistently been Panamanian. The same thing happened with the Protestant denominations: the 1972 Constitution required that the senior leadership of religious groups in Panama be exercised by native Panamanians.