Cannabidiol (CBD) has gained popularity in veterinary medicine for its potential to alleviate stress, pain, and inflammation in dogs. However, its oral administration is limited by hydrophobicity, variable absorption, and extensive first-pass metabolism, which requires optimized delivery methods to enhance efficacy. This study investigated the effects of daily oral supplementation of CBD oil and CBD gel (each at 4 mg/kg), compared to a placebo, over 14 days in shelter dogs subjected to solitary confinement-induced stress. Both CBD formulations appeared safe under the study conditions, with no adverse effects on hematological and biochemical parameters. Post-stress cortisol levels were significantly lower in CBD-treated groups compared to controls, with CBD-infused gel showing a pattern toward greater attenuation. Multivariate analysis revealed distinct blood profile shifts in CBD-treated dogs, with PCA loadings indicating associations between CBD supplementation and lymphocyte percentages and IgG levels. These findings support gel-based CBD as a promising strategy for stress modulation in dogs. Further studies should explore its pharmacokinetics and long-term immune effects to optimize veterinary applications.