The production methods for different isotopes vary, and only that for promethium-147 is given because it is the only isotope with industrial applications. Promethium-147 is produced in large quantities (compared to other isotopes) by bombarding uranium-235 with thermal neutrons. The output is relatively high, at 2.6% of the total product. Another way to produce promethium-147 is via neodymium-147, which decays to promethium-147 with a short half-life. Neodymium-147 can be obtained either by bombarding enriched neodymium-146 with thermal neutrons or by bombarding a uranium carbide target with energetic protons in a particle accelerator. Another method is to bombard uranium-238 with fast neutrons to cause fast fission, which, among multiple reaction products, creates promethium-147.

As early as the 1960s, Oak Ridge National Laboratory could produce 650 grams of promethium per year and was the world's only large-volume synthesis facility. Gram-scale production of promethium has been discontinued in the U.S. in the early 1980s, but will possibly be resumed after 2010 at the High Flux Isotope Reactor. Currently, Russia is the only country producing promethium-147 on a relatively large scale.

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