Introduction: Lidocaine–prilocaine cream effectively reduces vaccination pain, improving vaccination adherence and advocating for its routine use in healthcare settings. Methods: This review used PRISMA guidelines and the PICOT format to structure the analysis. The focus was on paediatric patients aged 0–12 months requiring intramuscular vaccinations, comparing the application of lidocaine–prilocaine cream to other interventions or no treatment. Data sources included MEDLINE, PUBMED, EMBASE, BMC, Research GATE, and Cochrane Library. Studies were selected based on predefined inclusion and exclusion criteria, with data extracted regarding participant demographics, pain assessment scales, and study conclusions. The Cochrane Risk of Bias Tool assessed study quality, while statistical analyses evaluated the effectiveness of the intervention. Results: Fifty studies were identified, with nine ultimately included in the analysis, involving 704 participants. The primary outcome was the effectiveness of lidocaine–prilocaine cream in reducing pain after vaccinations. Results showed a significant mean difference of −1.719 in pain scores for infants treated with lidocaine–prilocaine compared to those receiving other interventions. Behavioural indicators, such as crying duration and latency to the first cry, favoured the lidocaine–prilocaine group. Conclusions: Lidocaine–prilocaine cream effectively reduces vaccination pain, supporting its routine use in healthcare settings. Engaging parents can enhance vaccination adherence. Training healthcare professionals on lidocaine–prilocaine cream application and pain scales is vital for improving patient satisfaction. Further research is needed to evaluate the long-term effects of lidocaine–prilocaine cream on vaccination experiences and infant behavioural health.
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