Background: Rogamarga is one of the fundamental principles in Ayurveda that describes the pathway or site of disease manifestation. Madhyama Rogamarga comprises of Marma, Asthi, and Sandhi. It encompasses a wide spectrum of clinical conditions mainly involving vital structures, bones, joints, movement, and functional activity. Although classical texts describes diseases associated with Madhyama Rogamarga, clinical evidences regarding the predominance of individual symptoms/manifestations remains limited. Objective: To identify and assess the most predominant clinical manifestations in participants affected with Madhyama Rogamarga diseases. Materials and Methods: A cross-sectional observational study was conducted among patients attending the OP, IP & Medical camps of Sri Sri College of Ayurvedic Science and Research Hospital, Cuttack, Odisha. Eligible participants were assessed using structured questionnaire developed following an extensive review of Ayurvedic literature and validated by experts of Ayurveda Siddhanta and Samhita. A total of 511 participants were screened, out of which 320 were identified with Madhyama Rogamarga involvement. Clinical manifestations were analysed using descriptive statistics, and frequencies and the percentages were calculated. Results: Among the 320 participants with Madhyama Rogamarga involvement, Sthambha was observed as predominant manifestation (61.3%), followed by Cheshtanasha (42.8%), Shotha (26.3%), Janusandhi Shula (25.6%), and Katishula (23.1%). Sthambha was seen a nearly comparable distribution between mild (31.6%) and moderate (29.7%) grades. Conclusion: Sthambha was the most predominant clinical manifestation among participants affected with Madhyama Rogamarga, followed by Cheshtanasha, Shotha, Janusandhi Shula, and Katishula. Systematic assessment of these clinical manifestations helps for a clearer clinical understanding and characterization of Madhyama Rogamarga.