The name Comrie comes from a Gaelic phrase meaning flowing together, and the village sits at the confluence of three rivers: the Ruchill, the Lednock, and the Earn, which carries their combined water east to join the Tay. The setting is what Scots call a strath, a broad river valley with mountains on either side. To the north Ben Chonzie and the Grampian Mountains rise sharply. To the south the land opens into moorland and softer hills. This is one reason Comrie claims, with some justification, to be a Gateway to the Highlands. It is also the reason the ground here will not stay still.

In AD 79 the Roman general Agricola pushed north and built a fort and marching camp on what is now the outskirts of Comrie. It was part of a line of glen-blocking forts designed to seal off Highland exits, running from Drumquhassle in the south-west to Stracathro in the east. Some have argued that the famous Battle of Mons Graupius, where Agricola supposedly broke a Caledonian army, took place somewhere in Strathearn. The location has never been confirmed. James V of Scotland later came here every September to hunt deer; his consort Mary of Guise joined the hunting parties at Glenartney.

Comrie's early prosperity came from weaving and from cattle. River crossings made the village a natural staging post on the long drove roads that pushed Highland cattle south to the markets of the Scottish Lowlands and ultimately England. The Drummond family, Earls of Perth, owned much of the surrounding land from their seat at Drummond Castle south of Crieff. Then came the Highland Clearances. Glen Lednock alone had contained 21 separate settlements with 350 individual structures and 25 corn-drying kilns, all Gaelic-speaking. The Clearances of the 18th and 19th centuries emptied them. The ruins are still scattered through the hills above the village.

South of the village stands Cultybraggan Camp, which during the Second World War was POW Camp 21. This was a black camp, holding the most ardent Nazi prisoners, and in 1944 an anti-Nazi German POW named Wolfgang Rosterg was lynched there by fellow inmates, who were hanged after the war. A Waffen-SS prisoner named Heinrich Steinmeyer was held at Cultybraggan until 1948. In December 2016, decades after returning to Germany, Steinmeyer left Comrie £384,000 in his will. He wrote that the bequest was an expression of his gratitude to the people of Scotland for the kindness and generosity he had experienced as a prisoner of war. A local trust manages the legacy.

Every Hogmanay at midnight, the strongest men of Comrie carry burning birch poles through the village in a procession that local tradition holds is pre-Christian, possibly Pictish, intended to cleanse the village of evil spirits before the new year. The flaming torches are eventually thrown from Dalginross Bridge into the River Earn. Up in Glen Lednock, on the woodland trail to the Melville Monument, the river plunges through a deep gorge known as the Deil's Cauldron, the Devil's Kettle. Local legend gives the gorge a resident water-elf named Uris-chidh, who lures victims into the boiling pools. The walk past the cauldron is genuinely impressive. The water-elf is not optional.