Oxidative stress can impair calf health and performance, and oregano essential oil (OEO) has potential antioxidant activity. This study evaluated dietary OEO in a diquat-induced oxidative-stress model using 24 weaned male Holstein calves assigned to a 2 × 2 factorial design with OEO supplementation (0 or 8 g/day) and diquat challenge (saline or 8 mg/kg body weight). Growth performance, serum biochemical, antioxidant, oxidative-damage and inflammatory indices, hepatic Nrf2-related antioxidant gene expression, rumen microbiota, and rumen metabolomics were assessed. The results showed that growth responses were phase dependent: OEO increased overall average daily gain (ADG) and dry matter intake (DMI), whereas diquat reduced overall ADG; no OEO × diquat interaction was detected for overall growth outcomes. The OEO group had higher serum SOD, GSH-Px, and T-AOC levels and lower levels of selected oxidative-damage and inflammatory indices, although the responses varied by endpoint and time point. Hepatic RT-qPCR showed treatment-associated differences in Keap1, HMOX1, GCLC, GCLM, and SOD1 expression. Rumen 16S rRNA gene sequencing showed treatment-associated shifts in microbial community composition, whereas PICRUSt2 predicted differences in microbial functional potential, including amino-acid-metabolism-related functions. Untargeted metabolomics identified treatment-associated differences in rumen metabolite profiles and KEGG pathway-enrichment patterns. Correlation analysis indicated that OEO-associated characteristic metabolites were positively correlated with antioxidant markers and negatively correlated with oxidative-damage and pro-inflammatory indices. Overall, OEO supplementation was associated with improved antioxidant status and distinct rumen microbial-metabolic profiles in diquat-challenged calves, supporting its potential as a natural feed additive, while the involvement of specific molecular pathways requires further validation.