Background <p>Typhoid fever caused by <i>Salmonella enterica</i> serovar Typhi remains a major cause of febrile illness among children in low- and middle-income countries, particularly in South and Southeast Asia. The increasing emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains has substantially limited available treatment options and highlighted the need for effective oral therapies. Azithromycin and ceftriaxone are commonly used for uncomplicated typhoid fever in children; however, evidence comparing their efficacy and safety remains limited.</p> Objective <p>To compare the efficacy and safety of azithromycin versus ceftriaxone for the treatment of uncomplicated typhoid fever in children through a systematic review and meta-analysis of randomized controlled trials.</p> Methods <p>A comprehensive literature search was conducted in PubMed, the Cochrane Library, ClinicalTrials.gov, Google Scholar, and WHO ICTRP from inception to April 2026 in accordance with PRISMA 2020 guidelines. Randomized controlled trials comparing azithromycin with ceftriaxone in children under 18 years of age with uncomplicated typhoid fever were included. The primary outcome was the clinical cure rate. Secondary outcomes included fever clearance time, microbiological cure, relapse, and adverse events. Data extraction and risk of bias assessment using the Cochrane Risk of Bias 2 tool were performed independently by two reviewers. Meta<b>-</b>analysis was conducted using a random-effects model, and heterogeneity was assessed using the I² statistic.</p> Results <p>Six randomized controlled trials involving 492 children (azithromycin = 244; ceftriaxone = 248) were included. All studies were open-label trials conducted in Egypt, India, Pakistan, and Bangladesh. Overall risk of bias was judged to be of some concern, mainly due to the open-label study design. Meta-analysis showed no significant difference between azithromycin and ceftriaxone in clinical cure rate (RR = 0.98, 95% CI 0.93–1.03; <i>P</i> = 0.43) or fever clearance time. Similarly, microbiological cure and adverse event profiles were similar across groups but could not be formally pooled due to heterogeneous reporting. However, azithromycin was associated with fewer relapses than ceftriaxone, though this finding should be interpreted with caution given the low certainty of the evidence. The certainty of evidence was very low for fever clearance and low for the relapse rate. Heterogeneity varied across outcomes, with the highest for fever clearance time.</p> Conclusion <p>Azithromycin appears to have comparable efficacy and safety to ceftriaxone for the treatment of uncomplicated typhoid fever in children, with a trend toward fewer relapses that warrants cautious interpretation. Its oral administration may provide a practical alternative to parenteral ceftriaxone in endemic settings. Further large-scale randomized trials with standardized outcome reporting are needed to strengthen the current evidence base.</p> Clinical trial number <p>Not applicable.</p> Systematic review registration <p>PROSPERO Protocol Number: CRD420261383999.</p> Link <p><a href="https://www.crd.york.ac.uk/PROSPERO/view/CRD420261383999">https://www.crd.york.ac.uk/PROSPERO/view/CRD420261383999</a>.</p>