Successful endodontic therapy relies heavily on effective disinfection of the complex root canal system. While mechanical instrumentation addresses the main canal space, irrigation plays a critical role in accessing anatomical complexities where microorganisms persist in biofilm communities. This article reviews current evidence regarding the efficacy of various contemporary irrigation activation systems in eradicating biofilms from complex root canal anatomies. The limitations of conventional syringe irrigation are discussed, followed by an in-depth analysis of advanced activation technologies including ultrasonic, sonic, negative pressure, and laser-based systems. Their mechanisms of action, clinical efficacy, advantages, and limitations are examined through the lens of biofilm eradication in anatomical complexities such as isthmuses, lateral canals, and apical deltas. Current research suggests that activation techniques significantly improve irrigation efficacy compared to conventional methods, though no single system has demonstrated complete biofilm elimination in all anatomical variations. This review highlights the importance of understanding the physical and biological principles underlying irrigation activation to optimize clinical outcomes in endodontic therapy.