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Beyond the well‐defined role of the Eph (erythropoietin‐producing hepatocellular) receptor tyrosine kinases in developmental processes, cell motility, cell trafficking/adhesion, and cancer, nothing is known about their involvement in liver pathologies. During blood‐stage rodent malaria infection we have found that EphB2 transcripts and proteins were up‐regulated in the liver, a result likely driven by elevated surface expression on immune cells including macrophages. This was significant for malaria pathogenesis because EphB2–/– mice were protected from malaria‐induced liver fibrosis despite having a similar liver parasite burden compared with littermate control mice. This protection was correlated with a defect in the inflammatory potential of hepatocytes from EphB2–/– mice resulting in a reduction in adhesion molecules, chemokine/chemokine receptor RNA levels, and infiltration of leukocytes including macrophages/Kupffer cells, which mediate liver fibrosis during rodent malaria infections. These observations are recapitulated in the well‐established carbon tetrachloride model of liver fibrosis in which EphB2–/– carbon tetrachloride–treated mice showed a significant reduction of liver fibrosis compared to carbon tetrachloride–treated littermate mice. Depletion of macrophages by clodronate‐liposomes abrogates liver EphB2 messenger RNA and protein up‐regulation and fibrosis in malaria‐infected mice. Conclusion: During rodent malaria, EphB2 expression promotes malaria‐associated liver fibrosis; to our knowledge, our data are the first to implicate the EphB family of receptor tyrosine kinases in liver fibrosis or in the pathogenesis of malaria infection.