Aims: Recently, the cefixime–ofloxacin combination is approved by Drug Controller General of India to treat typhoid fever. We sought to evaluate the antimicrobial activity of cefixime–ofloxacin combination against Salmonella Typhi. Methods and Results: A total of 283 nonduplicate S. Typhi isolates collected during 2012–2014 were included in this study. Minimum inhibitory concentration (MIC) of cefixime and ofloxacin was determined by using broth microdilution method. Combinational testing was performed by using checkerboard assay. In checkerboard assay, synergistic activity was seen in 11% of isolates, while the majority of the isolate showed indifference and none of them showed antagonism. An in silico strategy, an alternative to the animal model, was carried out to understand drug interaction and toxicity. Molecular docking results elucidated that cefixime and ofloxacin are capable of inhibiting the cell wall synthesis and DNA replication, respectively. Computational ADMET analysis showed no toxicity and no drug–drug interaction between cefixime and ofloxacin. Conclusion: Cefixime–ofloxacin combination could be effective against moderately susceptible fluoroquinolone S. Typhi but not fluoroquinolone-resistant isolates. Significance and Impact of the Study: Cefixime–ofloxacin combination with no drug–drug interaction and nontoxic predicted through computational analysis did not show antagonism against S. Typhi in in vitro. Although this study showed no adverse effects with the cefixime–ofloxacin combination, further studies on pharmacokinetic and pharmacodynamic (PK-PD) parameters of cefixime and ofloxacin combination are warranted. © 2017 The Society for Applied Microbiology