Black mambas eat small mammals found in their African range, including rodents such as squirrels and others such as hyraxes, along with occasional birds. They kill their prey with venom, striking twice and injecting a neurotoxin, and they do not eat until their prey is paralyzed or dead.

Black mambas often take shelter in human structures and are unpredictable and aggressive in their behavior. The venom of black mambas is infamous for its danger to humans, and a human struck by a black mamba can die as quickly as 20 minutes later. If bitten, immediate medical attention is required, and life support may be required until the immune system recovers.