Hokkaidō was connected to northern Asia via Sakhalin, the large island to the north, and the Kuril Islands, a long archipelago reaching from the Kamchatka peninsula towards eastern Hokkaidō, during the glacial age. It is believed that humans moved into the region around 30,000 years ago, following the mammoths and bison that once roamed these parts. In the 12th or 13th century, influenced by both the burgeoning Japanese civilisation to the south and the hunting and fishing tribes to the north (in Sakhalin and beyond), a distinct culture formed. The people called themselves Ainu, which meant 'human' and their land Mosir, which meant 'world'.

Prior to 1869, the Japanese called the island Ezo (or Yezo) and its people emishi (basically, barbarians). Hokkaidō was a foreign land. As the Japanese empire solidified and expanded in the 14th and 15th centuries, many Japanese people moved north, lured by the promise of profit in trade. Conflicts erupted occasionally between the Ainu and the Japanese settlers, but they remained important trading partners: the Japanese coveted the dried fish, seaweed pelts and furs of the Ainu; the Ainu had come to depend on the iron goods imported from the south.

Then, in 1590, the Matsumae clan of northern Honshū was given permission by shogun Toyotomi Hideyoshi to extend their domain over the southern reach of Ezo – in order to better protect Japan from 'barbarian' attack. In 1604 the newly established Tokugawa shogunate granted the Matsumae clan exclusive trading rights in Ezo. With consolidated authority (and occasional force), the Matsumae were able to push forward with trade and production regulations that resulted in the Ainu working for the Japanese (in fisheries, for example) in order to receive the same goods they had previously acquired through trade.

Japanese authority crept ever northward throughout the 18th and 19th centuries, with colonialisation beginning in earnest following the Meiji Restoration. In 1869, the new government formally annexed Ezo, renamed it Hokkaidō ('northern sea territory'), and established the Kaitakushi (Development Commission) to promote settlement and introduce agriculture and manufacturing to the region. Among those who were encouraged to move north were the newly unemployed (and potentially troublesome) samurai class and luckless second sons (as first-born sons traditionally inherited everything).

The primary purpose of this push northward was to halt Russian expansion southward, but it was devastating for the Ainu. While the Ainu had previously been prohibited from dressing like Japanese – in order to distinguish them – new regulations demanded assimilation, banning the Ainu language and traditional ways of life.

Following the Japanese victory in the 1904–05 Russo-Japanese War, Japan took control of the whole of the island of Karafu-tō (now Sakhalin). By 1940, 400,000 Japanese were living there as part of a continuing colonial effort. In the final days of WWII, Russia recaptured Sakhalin, as well as the southern Kuril Islands, which were then part of Japan (and now referred to in Japan as the Northern Territories).

Still today Japan continues to dispute the ownership of the latter, which were captured after Japan's surrender to the Western European powers (Russia was not party to that treaty). The islands remain a point of contention between Japan and Russia, to the point that the two countries have yet to sign a peace treaty ending the war.

In September 2018, the island was hit by several major earthquakes, one of which caused a deadly landslide, ruptured highways, destroyed homes and buildings, and caused major power outages across the south and central parts of the island. Though the structural damage was quickly repaired, tourism dropped to a fraction of what it would have been as people avoided the area.