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Anecdotal evidence of beneficial behavioral and health effects of cannabidiol (CBD) use in companion animals has amplified the need to elucidate safety and potential impacts of CBD use. The purpose of this investigation was to determine the impact of industrial hemp-derived CBD administration on canine health and well-being. We hypothesized that CBD would produce beneficial effects on canine behavior without negatively impacting animal health. Dog treats were formulated to include CBD and shown to be palatable across a range of CBD inclusion levels. Dogs were supplemented with CBD treats and subjected to a noise-induced fear response test to assess potential anxiolytic effect of CBD. Behavioral response to the noise-induced fear response test was unaffected by CBD and did not support an anxiolytic effect of CBD when supplemented at 1.4 mg/kg BW/d. Next, triaxial accelerometers were fitted to dogs’ collars to assess the impact of CBD treats on voluntary daily activity. While voluntary daily activity of healthy adult dogs was unaffected by 1.8 and 4.5 mg CBD/kg BW/d, a reduction in daily scratching suggested a potential antipruritic effect of CBD. Potential impacts on canine health were also assessed by evaluating changes in the canine metabolome, hematology, and serum chemistry, and immune response upon exposure to a novel antigen. The canine metabolome, including amine/phenol, carbonyl, carboxyl, and hydroxyl metabolites, was altered with 4.5 mg CBD/kg BW/d and suggested an impact on glucose, amino acid, vitamin, and nucleotide metabolism. Hematological and clinical indices of health and serum immunoglobulins (IgG and IgM) were largely unaffected by 5 mg CBD/kg BW/d; however, elevated liver enzyme alkaline phosphatase may suggest altered liver function. These findings may be used to formulate recommendations for CBD use in a clinical environment, spur investigation into other potential therapeutic effects of CBD, and may serve as a foundation for the development of regulations on CBD use, all of which are essential to supporting the health and well-being of companion animals.