This review sought to provide an overview of proposed methods and protocols for processing surgical instruments contaminated with prions. A search of PubMed was conducted to identify studies published between January 1, 2012, and January 2, 2019, with no language restrictions and using varying combinations of the following terms: prions (Medical Subject Heading [MeSH]) OR decontamination (MeSH) OR cleaning OR disinfection OR sterilization. Articles were excluded if they did not involve medical device surfaces or describe the processing protocol. At least two reviewers independently selected articles, extracted data, and assessed data. A total of 627 articles published in peer-reviewed journals were identified. Of the 55 articles assessed for full-text eligibility, eight met the inclusion criteria. Only a few studies investigated protocols and methods for processing prion-contaminated medical devices; therefore, determining the best way to sterilize device surfaces and preserve the integrity of surgical instruments remains challenging. Moreover, the perspective of sterile processing department staff continues to be overlooked when designing studies.