The aim of this study was to provide an evidence-based answer to the question: “Is 3.6-mL volume of an anesthetic agent more effective than 1.8-mL volume in providing anesthesia for mandibular molars?” Following formulation of research question and keyword selection, a comprehensive search of the following databases was conducted: Cochrane library, PubMed, Scopus, Google Scholar, ProQuest, and Clinicaltrials.gov. Three-phase eligibility appraisal and quality assessment of the studies were carried out by 2 independent reviewers. To reduce clinical heterogeneity, the included studies were divided into 2 groups: studies on healthy teeth and studies on teeth with pulpitis. The data of included studies were statistically combined through meta-analysis using a fixed-effects model. A total of 20,778 records were initially retrieved from the search. Following screening and eligibility assessment, 8 studies met the eligibility criteria and were included for qualitative synthesis. Of those, 5 studies were qualified for meta-analysis. In the irreversible pulpitis group, increasing the volume of anesthetic agent from 1.8 to 3.6 mL significantly increased the success rate of inferior alveolar nerve block (risk ratio = 2.45, 95% CI: 1.67–3.59, p < .001). However, there was insufficient evidence to draw a conclusion regarding healthy teeth.