Introduction Scrub typhus is a bacterial mite-borne disease associated with poor clinical outcomes if not treated adequately. The study aimed to compare the time to defervescence, clinical failure, mortality and treatment-related adverse effects of two common drugs (doxycycline and azithromycin) used for its treatment. Methodology This was a systematic review and meta-analysis. All studies up to 20.03.2023 were screened for eligibility in Pubmed and Embase using a search string containing terms related to scrub typhus, doxycycline and azithromycin. After two phases of screening, all comparative studies where doxycycline and azithromycin were used to treat scrub typhus were included. The studies were critically appraised using standardised tools, and a meta-analysis was performed for time to defervescence (primary outcome), clinical failure, mortality and treatment-related adverse effects. Results Of 744 articles from two databases, ten were included in the meta-analysis. All but two studies had a high risk of bias. The meta-analysis for time to defervescence had a high heterogeneity and did not show any significant difference between doxycycline and azithromycin arms [Mean difference of -3.37 hours (95%CI: -10.31 to 3.57), p=0.34]. When the analysis was restricted to studies that included only severe scrub typhus, doxycycline was found to have a shorter time to defervescence [mean difference of -10.15 (95%CI: -19.83 to -0.46) hours, p=0.04]. Additionally, there was no difference between the two arms concerning clinical failure, mortality and treatment-related adverse effects. Conclusion The current data from studies with a high risk of bias did not find statistically significant differences in clinical outcomes between doxycycline and azithromycin for scrub typhus