Resistance training (RT) induces skeletal muscle adaptations but is often accompanied by soreness and inflammation that may deter consistent participation. Cannabidiol (CBD), a non-psychotropic cannabinoid with reported anti-inflammatory and analgesic properties, has gained popularity among athletes, yet limited evidence exists regarding its efficacy in exercise recovery. This study examined the effects of acute CBD supplementation on biomarkers of inflammation and muscle damage following a fatiguing RT protocol. Nine resistance-trained participants (7 males, 2 females) completed three randomized conditions: placebo, low-dose CBD (2 mg/kg), and high-dose CBD (10 mg/kg). Each trial consisted of eccentric back squats designed to induce delayed onset muscle soreness, with blood samples collected at baseline, 24, 48, and 72 hours post-exercise. Biomarkers analyzed included interleukin-6 (IL-6), interleukin-10 (IL-10), and myoglobin. Repeated measures ANOVA revealed no significant effects of dosage or time for IL-6. For IL-10, there was a significant main effect of dosage and a dosage × time interaction, with lower concentrations observed in both CBD conditions compared to placebo. Myoglobin demonstrated a significant effect of time, but no effect of dosage or interaction. These findings suggest that CBD supplementation did not alter IL-6 or myoglobin responses but was associated with reduced IL-10 levels, potentially blunting the typical anti-inflammatory cascade following exercise. While CBD shows promise as a recovery aid in some contexts, its effects in healthy, resistance-trained individuals appear complex and context-dependent. Further research with larger, more diverse cohorts is warranted to clarify CBD’s role in exercise-induced inflammation and recovery.