Sekhmet was usually depicted as a woman with the head of a lioness and naked human breasts, or wholly as a lioness. Occasionally, however, she was portrayed as a male deity with an erect penis. To symbolize her role as a goddess of fire, her statues were often carved from igneous rock such as basalt or granite.

Sekhmet's character incorporated both the beneficial and destructive aspects of fire, and by extension she was a goddess who could heal the sick or spread diseases. As goddess of war, she was adept at instilling fear in her enemies. In her beneficial aspect, she became fused with the cat-headed goddess Bast, who personified the fertilizing power of the sun and protected men from diseases. The relationship between Sekhmet and Bast could have been a parallel to the relationship between the sister goddesses Nephthys and Isis.

Sekhmet was also often associated with the cow-headed fertility goddess Hathor. According to one myth, the sun-god Ra commanded Hathor to destroy mankind for its disobedience. Sekhmet accompanied her, and in her fierce destructive heat became known as the Eye of Ra. Their joint slaughter was so severe and bloody that Ra repented. He was able to stop Hathor and Sekhmet from killing the remaining humans only by making Hathor and Sekhmet drunk on beer dyed with red ochre, which they drank because they believed it to be blood. It was speculated that this story reflected some ancient blood sacrifice ritual, but no physical evidence of this kind of practice in predynastic Egypt was ever discovered.

Sekhmet shared many common aspects with the Hindu goddess Kali and the ancient Near Eastern goddess Astarte.