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Purpose: This study aimed at exploring the pain and physiological responses exhibited during Ponseti manipulation and casting in clubfoot infants. In addition, we compared the efficacy of 2 nonpharmaceutical techniques (non-nutritive sucking and human care contact) for tackling these responses. Methods: The study included children with unilateral and bilateral idiopathic clubfeet between 15 days to 6 months of age. For comparisons, children were divided into control group without any intervention (group A), non-nutritive sucking group (group B), and human care contact group (group C). Pain score (Neonatal Infant Pain Score), heart rate (HR), and oxygen saturation (SpO2) was assessed before, during and 1 minute after casting. These measurements were compared using statistical methods. Results: There were 16 children (11 bilateral) in group A, 17 (10 bilateral) in group B, and 18 (8 bilateral) in group C. Before casting, the baseline parameters (Neonatal Infant Pain Score, HR, and SpO2) of the 3 groups were comparable. Groups B and C had a significant reduction in pain score at casting and in postcasting period when compared with group A (P<0.05). Group B (at casting—mean: 174.1/min, postcasting—mean: 168.2/min) had the lowest HR both during and after cast application. Group B had the highest SpO2 among all the 3 groups, both during casting (mean: 95.7%) and after casting (mean: 97.4%) (P<0.05). Conclusions: Infants exhibit moderate pain response and altered physiological responses during and after Ponseti casting. Non-nutritive sucking emerged as a better method to lessen these parameters when compared with the conventional technique and human care contact. Level of Evidence: Level II.