Although bismuth selenide occurs naturally (as the mineral guanajuatite) at the Santa Catarina Mine in Guanajuato, Mexico as well as some sites in the United States and Europe, such deposits are rare and contain a significant level of sulfur atoms as an impurity. For this reason, most bismuth selenide used in research into potential commercial applications is synthesized. Commercially-produced samples are available for use in research, but the concentration of selenium vacancies is heavily dependent upon growth conditions, and so bismuth selenide used for research is often synthesized in the laboratory.
A stoichiometric mixture of elemental bismuth and selenium, when heated above the melting points of these elements in the absence of air, will become a liquid that freezes to crystalline . Large single crystals of bismuth selenide can be prepared by the Bridgman–Stockbarger method.