Background Transcultural self-efficacy is a nurse’s perception of his or her own ability to accomplish activities effectively for culturally diverse clients. This self-efficacy may be affected by different factors, either positively or negatively. Quality care can be improved significantly when nurses provide patient-centered care that considers cultural background of the patients. Thus, this study aimed to assess perceived transcultural self-efficacy and its associated factors among nurses working at Jimma Medical Center. Methods Facility-based cross-sectional study with both quantitative and qualitative methods of data collection was conducted among 244 nurses and 10 key informants from 20 May to 20 June 2020. Bivariate and multivariable linear regression analyses were used to identify factors associated with transcultural self-efficacy. Qualitative data were coded and analyzed thematically. Quantitative results were integrated with qualitative results. Results A total of 236 nurses participated in the study making the response rate 96.7%. The mean transcultural self-efficacy score was 2.89 ± 0.59. Sex, work experience, intercultural communication, cultural sensitivity, interpersonal communication, and cultural motivation were significantly associated with transcultural self-efficacy. Ten in-depth interviews were conducted and the findings of qualitative data yielded four major themes. Conclusion The level of perceived transcultural self-efficacy was moderate among nurses. Transcultural self-efficacy of nurses varies with several factors including sex, experience, intercultural communication, cultural sensitivity, interpersonal communication, and cultural motivation. This calls for the need to offer transcultural nursing training for nurses.