The Cape Buffalo is a very powerful creature, demanding respect from even a pride of lions when paths cross. Other than humans, they have few natural predators and are capable of defending themselves against (and sometimes killing) lions. Lions do kill and eat buffalo regularly, but it typically takes multiple lions to bring down a single adult buffalo; only large male lions have been known to take down adult buffalo on their own. The leopard and spotted hyena are a threat only to newborn calves. The African Buffalo has never been domesticated.

Known as one of the "big five" in Africa, the African Buffalo is widely regarded as a very dangerous animal, as it gores and kills several people every year. Buffalo are sometimes reported to kill more people in Africa than any other animal, although the same claim is sometimes made of Hippopotami or Crocodiles. Buffalo are notorious among big game hunters as very dangerous animals, with wounded animals reported to ambush and attack pursuers. Buffalo occur from open savannah to thickly wooded country, and wallow when the opportunity presents itself.