Abstract Typhoid fever is a systemic intracellular infection caused by Salmonella enterica serotype Typhi. The emergence and spread of nalidixic acid-resistant S. Typhi (NARST) is challenging for clinicians in many countries owing to the lack of suitable treatment options. The aim of this study was to identify in vitro synergistic combinations of antibiotics against S. Typhi. In vitro time–kill studies were performed on three clinical NARST isolates and one type strain of nalidixic acid-susceptible S. Typhi (NASST) ATCC 9992 with ciprofloxacin, cefotaxime and azithromycin in various combinations. The combination of ciprofloxacin (0.012–0.375 μg/mL) and cefotaxime (0.063–0.125 μg/mL) against all three NARST strains and the NASST strain was significantly more effective in vitro in reducing bacterial counts by ≥3 log 10 colony-forming units at 24 h and showed synergistic effects. Combination therapy with ciprofloxacin and cefotaxime might be the treatment of choice for patients with typhoid fever. The combination of a fluoroquinolone and a β-lactam, which are directed against different targets, may improve efficacy compared with a fluoroquinolone alone and may reduce the chance of fluoroquinolone-resistant mutants emerging in patients with severe typhoid fever.