Itaconate (ITA), an immunomodulatory metabolite with known anti-inflammatory properties, has underexplored therapeutic or prophylactic potential against coronavirus disease 2019 (COVID-19). Using an interanimal transmission golden hamster model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced acute lung injury, we first assessed ITA changes in dNS1-RBD-vaccinated hamsters via metabolomic profiling. Then, we evaluated prophylactic intranasal (20 mg/kg at 9, 6, and 3 days before SARS-CoV-2 infection) and therapeutic intraperitoneal (100 mg/kg at 6, 24, and 48 hours post-infection) ITA administration, assessed by histopathology, transcriptomic, and metabolomic profiling, followed by multi-omics integration, including gene expression clustering, pathway enrichment, and cytokine/chemokine–metabolites correlation analyses. Public bronchoalveolar lavage fluid (BALF) single-cell RNA-sequencing (scRNA-seq) datasets from COVID-19 patients were re-analyzed to explore macrophage heterogeneity. Intranasal dNS1-RBD vaccine upregulated ITA levels, prompting further exploration of its immunomodulatory role. Both prophylactic and therapeutic ITA treatments significantly mitigated weight loss and improved lung pathology. Correlation analyses implied a potential regulatory crosstalk between fatty acid β-oxidation (FAO) and reduced inflammatory response. Re-analysis of BALF scRNA-seq dataset highlighted transcriptional networks involving PPARG, RARA, BHLHE41, TCF7L2, and ESRRA—genes linked to macrophage self-renewal and metabolic homeostasis, which appeared to be preserved in ITA-treated hamsters. These findings underscore ITA’s role in modulating immunometabolic responses, particularly through FAO-driven macrophage reprogramming, to attenuate SARS-CoV-2-induced lung damage. Together, this study provides insights into host-directed therapies targeting metabolic reprogramming to mitigate COVID-19 severity.