Cleft lip and palate (CLP) care is the longest sustained global effort in humanitarian surgical care. However, the relative cost-effectiveness of surgical delivery approaches remains largely unknown. We assessed the cost-effectiveness of two strategies of CLP surgical care delivery in low resource settings: medical mission and comprehensive care center. We evaluated the medical records and costs for 17 India-based medical missions and a Comprehensive Cleft Care Center in Guwahati, India, from Operation Smile, a humanitarian nongovernmental organization. Age, sex, diagnosis, and procedures were extracted and cost/Disability-Adjusted Life Year (DALY) averted was calculated using a provider's perspective. The disability weights for CLP from the Global Burden of Disease (GBD) 2010 update were used as the reference case. Sensitivity analysis was performed using various disability weights, age-weighting, discounting, and cost perspective. The medical missions treated 3503 patients for first-time cleft procedures and averted 6.00 DALYs per intervention with a cost-effectiveness of $247.42/DALY. The care center cohort included 2778 patients with first-time operations for CLP and averted a mean of 5.96 DALYs per intervention with a cost-effectiveness of $189.81/DALY. The Incremental Cost-Effectiveness Ratio (ICER) of choosing medical mission over care center is $462.55. The care center provides cleft care with a higher cost-effectiveness, although both models are highly cost-effective in India, in accordance with WHO guidelines. Compared to other global health interventions, cleft care is very cost-effective and investment in cleft surgery might be realistic and achievable in similar resource-constrained environments.