Estimates range as high as two million people, but more recent studies place that number closer to 200,000.Archaeological finds and testimonials by early European explorers describe diverse native isthmian groups exhibiting cultural variety and suggesting people developed by regular regional routes of commerce.

The indigenous peoples had no acquired immunity to diseases which had been chronic in Eurasian populations for centuries.

Rodrigo de Bastidas sailed westward from Venezuela in 1501 in search of gold, and became the first European to explore the isthmus of Panama.

The monumental monolithic sculptures at the Barriles (Chiriqui) site are also important traces of these ancient isthmian cultures.

Before Europeans arrived Panama was widely settled by Chibchan, Chocoan, and Cueva peoples.

The Isthmus of Panama was formed about three million years ago when the land bridge between North and South America finally became complete, and plants and animals gradually crossed it in both directions.

The existence of the isthmus affected the dispersal of people, agriculture and technology throughout the American continent from the appearance of the first hunters and collectors to the era of villages and cities.

The earliest discovered artifacts of indigenous peoples in Panama include Paleo-Indian projectile points.

Later central Panama was home to some of the first pottery-making in the Americas, for example the cultures at Monagrillo, which date back to 2500–1700 BC.

The best-known version is that a fishing village and its nearby beach bore the name "Panamá", which meant "an abundance of fish".

Captain Antonio Tello de Guzmán, while exploring the Pacific side in 1515, stopped in the small indigenous fishing town.

Panama was inhabited by several indigenous tribes prior to settlement by the Spanish in the 16th century.