Purpose: The study aimed to analyze the professional autonomy of Japanese nurses when caring for non-Japanese patients and to identify its contributing factors. Method: A descriptive cross-sectional design was used. Participants included 238 clinical nurses working at 27 hospitals in Japan. The Intercultural Sensitivity Scale (Chen and Starosta), and the Scale for Professional Autonomy in Nursing (Kikuchi and Harada) were used to measure intercultural sensitivity and professional autonomy. Stepwise multiple regression analysis was used to identify the most significant factors affecting professional autonomy. Results: Professional autonomy of Japanese nurses caring for non-Japanese patients was significantly lower than when caring for Japanese patients (142.84 vs. 172.85; p < .001). Contributing factors were intercultural sensitivity (p < .001), length of nurse experience (p < .05), and availability of interpretation service (p < .05). Conclusion: Incorporating transcultural nursing content into training programs in schools and hospitals could enhance professional autonomy of Japanese nurses by promoting intercultural sensitivity.