The Catskills began existence as a river delta 350 million years ago. Streams flowing off the then-mighty Acadian Mountains deposited sediment where the river met a sea (now the Allegheny Plateau. Eventually the Taconics eroded to their present size and the waters dried up, leaving a mostly flat plain.
During this time period, a meteor is believed to have struck the area. Panther Mountain is the remains of its crater.
Two hundred million years ago, as continental drift pushed up the Appalachians, the delta region rose almost uniformly into a plateau rather than breaking up into smaller mountains. Streams that formed over time eroded gaps and valleys, leaving today's "mountains."
The next great change in the Catskill landscape was caused by the most recent of four periods of glaciation, the Wisconsin. Every mountain except Slide (and perhaps West Kill) was covered. The glaciers left behind lakes when they melted, some of which became reservoirs in the 20th century.
Some geologists also believe the glaciers scoured off sedimentary layers that may have contained coal, noting the surfeit of coal to the south in Pennsylvania and that the white quartz pebbles found atop Slide Mountain are often an indicator that one has reached the bottom of a coal bed in those regions.
While the matter has yet to be fully researched, there seems to have been no large-scale long-term Native American presence in the mountains. The local Mohican and Munsee tribes used land and water routes through the mountains to get to the places beyond them, hunted the abundant game and used the mountains in some of their rituals, but in general chose not to live there due to the difficulty of farming the land.