Santarém's Maestro Wilson Fonseca Airport (STM) receives flights from Belém and Manaus operated by Azul and LATAM. Journey times are around an hour from either city. Book in advance as the route can fill up.
The classic way to arrive is by river boat. Boats depart regularly from Belém (about 48 hours, downstream) and Manaus (about 36 hours, also downstream going eastward). The boats have hammock class and basic cabin class; bring a hammock, a lock for your bag, and food to supplement what is sold on board. The journey itself is the point — the river, the forest, the sunsets.
The BR-163 road from Cuiabá is partially paved but long sections remain dirt or gravel, and travel is difficult in the wet season. This route is not recommended for most visitors.