A classical dance-drama, Kathakali, which originated from the southern Indian state of Kerala, is a captivating art form widely celebrated for its vibrant performances and elaborate makeup. Like other dance-drama forms such as Yakshagana, the makeup in Kathakali is a meticulous process designed to evoke a superhuman effect. The color combination, line, and stroke applied on the artist’s face play a pivotal role in this dance-drama in visual communication and storytelling. Mercury sulfide, lead sulfide, arsenic disulfide, carbon, and lead are some of the essential chemicals or chemical compounds in the Kathakali makeup. Many studies have already reported the toxicological/dermatological effects of these compounds. Since the entire makeup and performance routine spans 3–10 h, the level of exposure by artists to these chemicals is a dare concern. In that context, the present study was conducted to document the traditional makeup routine of the Kathakali. The study also examines the toxicological effects of the routine makeup materials used in the art form. Further the study also tries to identify factors that contribute to various physical discomforts among the performing artists. The study used custom-made questionnaire survey among 50% of the registered performing artists within the state of Kerala. The result emphasizes the generational gap among the artists that could be a threat to sustaining the art form. The result also necessitates efforts to promote gender inclusivity within Kathakali. Enhancing financial support and welfare and pension schemes for the artists are also a times need. Prolonged exposure to traditional makeup substances such as manayola (orpiment), chayilyam (mercury sulfide), and kunkumam (vermilion) is notably creating physical discomfort to the artists.