Background and Objectives Empathy, or the ability to understand the patient’s pain, is a critical component in a nurse’s repertoire of skills during patient care. Indian Nurses face challenges in practicing empathetic communication with patients due to a shortage of resources, skewed nurse-patient ratio and cultural differences. While clinical skills training is imparted to Indian Nurses, there is limited training on soft skills. Studies have proven that Games and Virtual Reality are powerful tools for imparting essential soft skills including empathy to nurses. The core purpose of this research was to identity the differences in the response to game-based learning among male and female nursing professionals. Methods: Three role-play game prototypes were designed for nurses to practice empathetic behaviour with a cancer patient. These were tested via random sampling on 90 nurses (36 Males and 54 Females). A learner feedback form was administered to the nurses to determine how nurses of different gender respond on dimensions of usability, contextual alignment, engagement and immersion, perceived learnability to the game interventions. Results and Conclusion: In an earlier study, the learner feedback form was proven to be reliable at Cronbach’s Alpha > 0.70. Based on the test results, the data was found not to be normally distributed, therefore a nonparametric test was required. The Mann–Whitney Test performed determined that female nurses were found to have a more positive response on all factors with respect to role-playing games, regardless of medium.