The city is among the oldest settlements in Central Asia. Osh was known as early as the 8th century as a center for silk production along the Silk Road. The famous trading route crossed Alay Mountains (part of the ancient Mount Imeon) to reach Kashgar to the east. In modern times, Osh has become also the starting point of the Pamir Highway crossing Pamir Mountains to end in Khorog, Tajikistan.

Babur, founder of the Mughal dynasty of Indian emperors and descendant of Timurlane, was born in nearby Andijan (Uzbekistan) in the Fergana Valley and set out from there on his conquest of northern India. He allegedly pondered his future on Sulayman Mountain, concluding that the confines of the Fergana would cramp his aspirations as a descendant of famous conquering warrior princes. He wrote of the city:

"There are many sayings about the excellence of Osh. On the southeastern side of the Osh fortress is a well-proportioned mountain called Bara-Koh, where, on its summit, Sultan Mahmud Khan built a pavilion. Farther down, on a spur of the same mountain, I had a porticoed pavilion built in 902 (1496-7)"

The city was occupied and annexed by the Russian Empire in 1876 when Russia overwhelmed the Central Asian khanates during the so-called Great Game - the contest between Britain and Russia for dominance in Central Asia.

In 1990, shortly before the end of Soviet power in Central Asia, Osh and its environs experienced bloody ethnic clashes between the Kyrgyz and the Uzbeks, causing on the order of 1000 deaths. Fortunately, no open violent ethnic conflicts have occurred in Osh since that time.