Prospective time–trend analyses on shifting etiology and trends of drug resistance in enteric fever are scarce. Using published and unpublished datasets from Nepal, we performed a systematic review and meta-analysis to understand the trends in etiology and resistance to antimicrobials that have occurred since 1993. Thirty-two studies involving 21 067 Salmonella enterica serotype Typhi (ST) and S. enterica serotype Paratyphi A (SPA) isolates were included. There was an increasing trend in enteric fever caused by SPA during the last 2 decades (P < .01). We observed sharply increasing trends in resistance to nalidixic acid and ciprofloxacin for both ST and SPA. In contrast, multi-drug resistance (MDR), resistance to traditional first-line antibiotics such as chloramphenicol and co-trimoxazole have significantly decreased for both organisms. The resistance to ceftriaxone has remained low, suggesting it is likely to remain useful as a reserve antibiotic for treatment. Trends in decreasing resistance to traditional first-line antibiotics and decreasing MDR provide an opportunity to reconsider these first-line antimicrobials as therapeutic options.