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Despite the global increase in cat ownership, some cats exhibit owner-directed aggression, resulting in caregiver injury, infection, and anxiety. Severe cases are commonly treated with selective serotonin reuptake inhibitors such as fluoxetine; however, adverse effects, particularly transient anorexia, often discourage treatment initiation. Cannabidiol (CBD), a natural compound with reported anxiolytic properties and minimal anorexic effects, may represent an alternative therapy. This study aimed to characterise owner-directed feline aggression in Thailand, identify associated factors, and compare the efficacy of CBD with fluoxetine. Most caregivers were females aged 20-40 years, and most cats were neutered mixed-breeds aged 1-6 years living indoors in multi-human and multi-cat households. For demographic variables, only human-cat interactions (e.g., petting) were significantly associated with aggression. Handling-induced aggression was universal, with grooming as the most common trigger (56%). In a single-blind, 4-8-week trial, 100 cats were randomly assigned to control, CBD 1 mg/kg/day, CBD 2 mg/kg/day, fluoxetine 0.5-1 mg/kg/day, or combined CBD and fluoxetine. Aggression scores decreased significantly in all treatment groups compared with control (p < 0.05), with no differences among active treatments. CBD at 1 mg/kg/day showed efficacy comparable to fluoxetine without anorexic effects.