Chemical debridement is considered one of the most important steps during root canal treatment to target unreached areas and provide thorough disinfection of the canals. The efficiency of this step efficiency can be increased using different agitation and irrigation techniques/devices. This comprehensive review aimed to summarize the effect of various irrigant activation and agitation techniques/devices on endodontic treatment outcomes. Using mechanical active irrigation, which enables the activation or agitation of the irrigating solution, is beneficial in root canal treatment by increasing the efficiency of delivering the irrigant up to working length and ensuring isthmus cleanliness. However, considerable variation was noticed between the protocols used in each technique with a lack of well-designed randomized clinical trials to focus on the long-term outcome. Moreover, a low level of evidence was noticed regarding the effectiveness of certain activation techniques over others. Therefore, each study needs to be carefully weighed before using its results and embracing its conclusion. Future studies need to focus more on the antimicrobial effect of each technique and its effect on the healing of apical periodontitis. Also, recent advances, such as multisonic and laser activation, are promising tools that need more clinical investigations to show their efficiency.