The recent COVID-19 pandemic has posed unprecedented challenges to healthcare professionals worldwide, by bringing changes in both their personal and professional lives. Motivation has become a driving factor along with cognitive flexibility during such demanding situations. Little importance has been given to the personality dimension while assessing these aspects, especially in the Indian context. The principal aim of this paper is to understand the relationship between personality, cognitive flexibility, and motivation among medical professionals during the COVID-19 Pandemic. A correlational research design was used to conduct the research, and a snowball sampling technique was used to collect the data from a sample size of 204 medical professionals, consisting of 101 nurses and 103 doctors, working as frontline workers. The variables were assessed using the Neo Five-Factor Inventory, the Cognitive Flexibility Inventory, the Work Extrinsic and Intrinsic Motivation Questionnaire. A nonparametric test of correlation was used. The research findings revealed that among medical professionals, certain personality factors, cognitive flexibility, and motivation share a significant relationship. Cognitive flexibility and motivation were found to be significantly correlated. There was no significant difference in cognitive flexibility and motivation among doctors and nurses. There was a significant difference in neuroticism between the groups. The findings will help in gaining a clearer insight into the needs of medical professionals in India, by facilitating the development of appropriate training interventions for medical professionals to be better equipped for similar crisis situations in the future.