The ruins near Desfina have been identified as those of ancient Echedameia and Medeon — two towns destroyed by Philip II of Macedon around 355–346 BC during the Third Sacred War and never rebuilt. Philip came through this part of Phocis with particular thoroughness, and both settlements simply ceased to exist as inhabited places after his forces were done with them. Four kilometers to the east of modern Desfina, Late Mycenaean ruins at Kastrouli have been linked to Homeric Anemoreia, mentioned in the Iliad. The deeper history of this peninsula, reaching back through Bronze Age settlements to the Mycenaean period, means that the plateau Desfina stands on has been occupied in various forms for more than three thousand years. The current town's name derives from the peninsula itself — the Desfina Peninsula juts southward into the Gulf of Corinth, and the town takes its name from the land that holds it.

In 1821, when the Greek War of Independence began against Ottoman rule, Desfina had its own martyr. Bishop Isaias of Salona — Salona being the old name for nearby Amphissa — was one of the most significant figures of the revolution in Central Greece. He fought for the liberation of Desfina, encouraged Athanasios Diakos before the battle of Alamana, and gave the signal for the beginning of the revolution in the region of Prophet Daniel. The Turks executed him on 22 April 1821. His residence in Desfina has been preserved and converted into a museum. The town's football club, founded in 1973, carries his name: Isaias Desfina. The Monastery of Timios Prodromos — the Honest Precursor, meaning John the Baptist — also played a role in the revolution and remains one of the settlement's important landmarks, along with a 12th-century Byzantine church near Saint Haralampos.

The geography of Desfina is its most immediate quality. At 680 meters, the town sits on a plateau that is genuinely elevated — the Gulf of Corinth is close but below, and Mount Parnassus rises to the north above Delphi, just seven kilometers away. The central square dates to the 19th century and offers a direct view of the mountain. The cafes and taverns encircling it are the social center of the town in the way that Greek village squares have been for generations — a place to sit, drink coffee, and argue about the weather with the same view of Parnassus that residents have had for centuries. The climate at this altitude is noticeably cooler than the coast, which historically made Desfina a summer retreat for people from the surrounding lowlands.

Before the aluminum plant at nearby Distomo transformed the regional economy in the 1950s and '60s, Desfina's residents lived primarily from animal breeding and agriculture. The traditional products of the area — olives and olive oil, grapes and wine, honey, cheese, bakery goods, and meat — remain the things Desfina is known for locally. Many people from the area now commute to work at the Aluminium of Greece facility. The Cultural Association Desfina I Proodos ('The Progress'), founded in 1979, now has around 200 members and runs a choir with both adult and children's sections. Every summer the town hosts a traditional concert for Greek clarino — the Greek clarinet — which draws audiences from the surrounding region. The Dormition of the Virgin on 15 August is the biggest celebration, with a traditional dance in the town center.

For a village of this size, Desfina's list of notable residents is striking. The painter Spyros Papaloukas, born here in 1892, became one of the significant figures in 20th-century Greek art, known for his landscapes and his years spent on Mount Athos documenting monastic life; his residence in the village has been preserved. Lucas Papademos, the economist who served as Prime Minister of Greece from 2011 to 2012 during the debt crisis, has family roots here — the Papademos family is from Desfina. The novelist and poet Giorgos Ch. Theocharis was also born here. And Bishop Isaias of Salona, who died for the revolution he helped begin, remains the figure the town most prominently claims — his name on its football club, his house a museum, his memory local and specific in the way that small towns preserve their dead.