Non-syndromic orofacial clefts (NSOC) are common craniofacial birth defects, and result from both genetic and environmental factors. NSOC include three major sub-phenotypes: non-syndromic cleft lip with palate (NSCLP), non-syndromic cleft lip only (NSCLO) and non-syndromic cleft palate only (NSCPO), NSCLP and NSCLO are also sometimes grouped as non-syndromic cleft lip with or without cleft palate (NSCL/P) based on epidemiology. Currently known loci only explain a limited proportion of the heritability of NSOC. Further, differences in genetic susceptibility among the sub-phenotypes are poorly characterized. We performed a multi-ancestry GWAS meta-analysis on 44,094 individuals (9,381 cases, 28,510 controls, 2042 case-parent trios and 18 multiplex pedigrees) of East Asian, European, Latin and South American, and African ancestry for both NSOC and subtypes. We identified 50 loci, including 11 novel loci: four loci ( CALD1 , SHH , NRG1 and LINC00320 ) associated with both NSOC and NSCL/P, two loci ( NTRK1 and RUNX1 ) only associated with NSOC, four loci ( HMGCR , PRICKLE1 , SOX9 and MYH9 ) only associated with NSCL/P and one locus ( ALX1 ) specifically associated with NSCLO. Five of the novel loci are located in regions containing genes associated with syndromic orofacial clefts ( SHH , NTRK1, CALD1, ALX1 and SOX9 ); seven of the novel loci are located in regions containing genes-implicated in craniofacial development ( HMGCR, SHH, PRICKLE1, ALX1, SOX9, RUNX1, MYH9 ). Genetic correlation and colocalization analyses revealed an overlap between signals associated with NSCLO, NSCPO and NSCLP, but there were also notable differences, emphasizing the complexity of common and distinct genetic processes affecting lip and palate development.