Enhancer-promoter interactions preferentially occur within boundary-insulated topologically associating domains (TADs), limiting inter-TAD interactions. Enhancer clusters in linear proximity, termed super-enhancers (SEs), ensure high target gene expression levels. Little is known about SE topological regulatory impact during craniofacial development. Here, we identify 2232 genome-wide putative SEs in mouse cranial neural crest cells (CNCCs), 147 of which target genes establishing CNCC positional identity during face formation. In second pharyngeal arch (PA2) CNCCs, a multiple SE-containing region, partitioned intoHoxaInter-TAD Regulatory Element 1 and 2 (HIRE1 and HIRE2), establishes long-range inter-TAD interactions selectively withHoxa2, that is required for external and middle ear structures. HIRE2 deletion in aHoxa2haploinsufficient background results in microtia. HIRE1 deletion phenocopies the full homeoticHoxa2knockout phenotype and induces PA3 and PA4 CNCC abnormalities correlating withHoxa2andHoxa3transcriptional downregulation. Thus, SEs can overcome TAD insulation and regulate anteriorHoxagene collinear expression in a CNCC subpopulation-specific manner during craniofacial development.