Lion predation on cattle causes severe human–wildlife conflict that results in retaliatory persecution throughout the lion’s geographic range. Cattle closely resemble the body size, shape, and herding patterns of preferred lion prey species. We studied cattle depredation patterns in Botswana’s Okavango Delta and tested whether lions exhibited specific preferences based on cattle demographic characteristics (sex and age), as well as morphological traits (body mass, horn length, and pelage patterns). We also tested whether human disturbance of kills influenced lion energy intake and whether depredation circumstances influenced loss levels. Lions predominantly killed cattle at night (87.1%) and exhibited no preference for either sex. Overall, bulls and calves were most preferred, whereas heifers were significantly avoided, as were cattle with uniform colour patterns. Cattle with mottled pelage patterns were most preferred, especially among free-roaming herds. Preferences were context-specific, with lions preferring inexperienced calves during enclosure attacks (including multiple cases of surplus killing) and free-roaming bulls and oxen. About 13% of adult cattle had no horns, and these were preferentially targeted by lions, while cattle with short horns were killed in accordance with their availability and long horned cattle were highly avoided. The contemporary morphology of Tswana cattle that resulted from unnatural selective pressures during domestication does not offer effective antipredatory protection. Human disturbance of feeding soon after kills occurred reduced cattle carcass consumption by >40% (or about 30 kg per carcass per lion). Lions killed significantly more cattle in nonfortified enclosures than in the veldt, although this was influenced by surplus killing. Our results suggest that cattle predation by lions is driven by availability and cavalier husbandry practices, coupled with morphological features associated with facilitating easy husbandry. Cattle no longer exhibit the key features that enabled their ancestors to coexist with large predators and are now reliant upon humans to perform critical antipredator activities. Hence, the responsibility for mitigating human–wildlife conflict involving lions and cattle lies with people in either breeding traits that minimise predation or adequately protecting their cattle.