Quorum sensing (QS) is a sophisticated bacterial communication system that regulates behaviors critical to pathogenicity, including biofilm formation, virulence, and antibiotic resistance. This review explores QS's pivotal role in polymicrobial infections, where interspecies interactions significantly enhance antibiotic resistance. It delves into the mechanisms of QS, focusing on acyl-homoserine lactones (AHLs) in Gram-negative bacteria and autoinducing peptides (AIPs) in Gram-positive bacteria, highlighting their contributions to biofilm-associated antibiotic resistance. The challenges presented by polymicrobial infections, such as those in cystic fibrosis lung infections, chronic wound infections, and medical device-associated infections, are analyzed in detail. Laboratory models, including flow cells, static biofilm systems, and mammalian models, are discussed as tools to study the interplay between QS and antibiotic resistance in controlled environments. Promising therapeutic approaches, particularly quorum sensing inhibitors (QSIs) like furanones, AHL analogs, and natural compounds such as flavonoids, are emphasized for their potential to disrupt bacterial communication, reduce virulence, and enhance antibiotic efficacy. Case studies demonstrating the efficacy of QSIs in both laboratory and clinical contexts are presented, underscoring their potential to combat recalcitrant infections. This review also considers the economic and healthcare burden posed by biofilm-induced antibiotic resistance, advocating for innovative strategies to mitigate this global challenge. By reviewing the complex interplay between QS and polymicrobial antibiotic resistance, this paper aims to advance therapeutic strategies and foster a deeper understanding of the mechanisms underpinning bacterial communication.