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The earliest known settlement at this location was the ancient Greek city of Cius, which Philip V of Macedon granted to Prusias, the King of Bithynia, in 202 BC. Prusias rebuilt the city and renamed it Prusa (). After 128 years of Bithynian rule, Nicomedes IV, the last King of Bithynia, bequeathed the entire kingdom to the Roman Empire in 74 BC.

Bursa became the first major capital city of the early Ottoman Empire following its capture from the Byzantines in 1326. As a result, the city witnessed a considerable amount of urban growth throughout the 14th century. After conquering Edirne (Adrianople) in 1365 the Ottomans turned it into a joint capital city for governing their European realms, but Bursa remained the most important Anatolian administrative and commercial center even after it lost its status as the sole Ottoman capital. The Ottoman sultan Bayezid I built the Bayezid Külliyesi (Bayezid I theological complex) in Bursa between 1390 and 1395 and the Ulu Cami (Great Mosque) between 1396 and 1400. Bursa remained to be the most important administrative and commercial center in the empire until Mehmed II conquered Constantinople in 1453. The population of Bursa was 45,000 in 1487.

During the Ottoman period, Bursa continued to be the source of most royal silk products. Aside from the local silk production, the city imported raw silk from Iran, and occasionally from China, and was the main production center for the kaftans, pillows, embroidery and other silk products for the Ottoman palaces until the 17th century.

Following the foundation of the Republic of Turkey in 1923, Bursa became one of the industrial centers of the country. The economic development of the city was followed by population growth and Bursa became the 4th most populous city in Turkey.

The city has traditionally been a pole of attraction, and was a major center for refugees from various ethnic backgrounds who immigrated to Anatolia from the Balkans during the loss of the Ottoman territories in Europe between the late 19th and early 20th centuries. The most recent arrival of Balkan Turks took place in the 1940s until the 1990s, when the communist regime in Bulgaria expelled approximately 150,000 Bulgarian Turks to Turkey. About one-third of these 150,000 Bulgarian Turkish refugees eventually settled in Bursa.