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This systematic review and meta-analysis aimed to investigate the necessity of histamine-2 antagonists (H2As) in paclitaxel premedication protocols, particularly in preventing hypersensitivity reactions (HSRs). The research question addressed whether the inclusion of H2As significantly reduces the incidence of HSRs associated with paclitaxel treatment. A comprehensive literature search of MEDLINE, Cochrane and Web of Science databases was conducted to identify studies on prophylactic H2As for paclitaxel-induced HSRs up to December 2023. Studies were included based on predefined criteria, including adult patients with cancer receiving paclitaxel infusions. Quality of included studies was evaluated using the Risk Of Bias In Non-randomised Studies–of Interventions tool and results were generated through a random effects statistical model. Six studies meeting the inclusion criteria were included in the meta-analysis. The analysis revealed no statistically significant difference in the incidence of grade III or higher HSRs (risk ratio, RR 1.04, 95% CI 0.65 to 1.67) or all-grade HSRs (RR 1.40, 95% CI 0.82 to 2.39) between patients receiving H2As as part of their premedication protocol and those without H2A blockade. Minimal heterogeneity was observed for grade III reactions (I²=0.0%, p=0.669), while high heterogeneity was noted for all-grade reactions (I²=73.4%, p=0.002). Subgroup analysis showed minimal heterogeneity with all-grade reactions once prospective studies were excluded (I2=0.0%, p=0.689). This meta-analysis supports the safe omission of H2As, particularly ranitidine, from paclitaxel premedication protocols without compromising patient safety in terms of HSRs.