Early stages of host–virus interactions in peripheral tissues, such as the liver, are critical yet understudied determinants of alphavirus pathogenesis. We utilized a liver organ-on-a-chip (OOC) model consisting of primary human hepatocytes (PHHs) and Kupffer cells (KCs) to enable time-resolved tracking of Venezuelan equine encephalitis virus vaccine strain TC-83 (VEEV TC-83) replication kinetics, tissue damage, and host immunopathology. This platform was employed to evaluate the host-directed therapeutic Omaveloxolone (OMA), a known nuclear factor erythroid 2-related factor 2 (Nrf2) activator. Productive VEEV infection induced acute liver injury, indicated by parallel increases in supernatant alanine aminotransferase (ALT) and lactate dehydrogenase (LDH), alongside the newly identified pathogen-associated biomarkers $\gamma$-enolase (ENO2) and complement factor H-related protein 3 (CFHR3). Post-infection treatment with OMA within a nontoxic range altered inflammatory responses and modestly reduced viral load during the early stages, although this inhibitory efficacy was lost at later time points. Collectively, this OOC model enables the investigation of organ-specific events, demonstrating that peripheral liver responses to VEEV involve coordinated inflammatory and proteomic alterations that culminate in acute liver injury, potentially contributing to systemic inflammation and overall alphavirus disease severity.