Syrian hamsters and gerbils are animal models for Opisthorchis viverrini infection. In both models, the parasites develop into adults with different pathologies of the hepatobiliary system. However, no comparative pathological studies have yet been completed. We therefore investigated host interaction through the susceptibility and pathological changes of Syrian hamsters and gerbils infected with 50 O. viverrini metacercariae for 30, 60, and 90 days post-infection. Animals were sacrificed at each time point for comparative study. Susceptibility and infectivity were investigated through worm burden. Parasite morphology and reproductive organs were stained with carmine and observed under light microscopy. Reproductive organs and eggs per worm were counted to confirm worm maturity. Bile acid components of both animal groups were analyzed by thin-layer chromatography. The results showed that infection in gerbils was of greater severity than in Syrian hamsters by observation of bile obstruction, enlargement of the gallbladder and common bile duct, and generation of fibrosis and cirrhosis. The worm burden of infected gerbils was lower than that observed in Syrian hamsters. Infectivity in both Syrian hamsters and gerbils was 100% with infection by 50 metacercariae; whereas with 10 metacercariae, the infectivity in gerbils was zero to very low, but still 100% in Syrian hamsters. The largest body size of worms, and the largest ovary and testes areas, was correlated with eggs per gram of feces and eggs per worm. The bile acid components cholic acid and chenodeoxycholic acid were undetectable in gerbils. The present study suggests that although Syrian hamsters, usually the host selection for an animal model, are susceptible to O. viverrini infection, infected gerbils produce worms that mature more rapidly, have larger body sizes, and more fully developed reproductive organs; this may be caused by the difference in bile acid components.