Microbial communities in the oral cavity exhibit complex interspecies interactions that significantly influence biofilm dynamics, pathogenesis, and therapeutic outcomes. Among these, the cross-kingdom interaction between Candida albicans and Streptococcus mutans has drawn increasing attention due to its role in exacerbating dental caries, particularly early childhood caries (ECC) and root caries. This chapter summarizes the synergistic interplay between these two oral pathogens, emphasizing their physical, metabolic, and molecular interactions. Given the intricate dynamics and clinical relevance of C. albicans–S. mutans interactions, we also explore emerging therapeutic strategies, ranging from natural compounds and nanomaterials to antimicrobial peptides, probiotics, and phototherapies. A deeper understanding of cross-kingdom communication offers novel insights into managing oral diseases and developing innovative interventions.