Patients with end-stage renal disease requiring hemodialysis undergo life-sustaining renal replacement therapy to maintain physiological homeostasis. Intradialytic discomfort represents the predominant physical and psychological source of pain associated with hemodialysis procedures, with intensity noted particularly during cannulation of the arteriovenous fistula, which remains the gold standard modality for vascular access. These individuals perpetually endure procedural pain, substantially compromising the quality-of-life metrics and, in the extreme, refraining from adhering to this life-preserving therapy. Thus, pain management is of paramount importance. The eutectic mixture of local anesthetics (EMLA) cream is a topical formulation comprising 2.5% lidocaine and 2.5% prilocaine, designed for enhanced dermal penetration to provide effective local analgesia during percutaneous procedures. This study aims to systematically analyze the safety and efficacy of EMLA cream as pain control in patients undergoing hemodialysis. This review was conducted in adherence to the PRISMA guidelines. The literature search was performed across electronic databases, including PubMed, ScienceDirect, and Scopus. Forest plots were generated to illustrate the pooled effect estimates for each outcome of interest using R software and Review Manager 5.4. Seven randomized controlled trials were deemed appropriate for review and meta-analysis, amounting to 1,375 patients. In comparison to placebo and alternative local anesthetics, pain intensity was lower in the EMLA group (mean difference [95% CI] of -2.58 [-3.22,-1.94], p<0.00001 and -0.99 [-1.57,-0.42], p=0.0007, respectively). EMLA provided similar pain reduction as nonpharmacological approaches did, although this comparison did not reach a statistical significance (mean difference [95% CI] of -0.26 [-1.98, 1.45], p=0.76). Concerning safety considerations, EMLA showed an acceptable adverse event profile with a low incidence of local cutaneous reactions (pooled proportion of 7% [95% CI 0.00–0.15], I2 =75.1%, p=0.0012). EMLA cream provides effective pain management during arteriovenous fistula cannulation in adult hemodialysis patients while demonstrating favorable patient tolerability and simple application in clinical practice.