The Tyet first appears in the archaeological record during the Predynastic period, before the unification of Egypt under King Narmer around 3100 BCE, though its earliest secure example comes from a First Dynasty tomb at Helwan, excavated by the Egyptologist Zaki Saad in the 1940s. This example predates the first written references to Isis herself, and the symbol may not have been connected with the goddess at that early stage. By the Third Dynasty of the Old Kingdom, roughly 2686 to 2613 BCE, the Tyet was already a popular decorative motif, appearing alongside the ankh and the djed pillar on temple walls, columns, sarcophagi, and shrines. In these early contexts it was sometimes combined with the bovine faces of the goddesses Bat and Hathor, the cow goddesses of fertility and music, and it served as a badge of office for the kherep-ah, the palace manager who oversaw the royal household. The symbol thus began its life not as a funerary amulet but as an administrative and decorative emblem, a knot that secured things and marked authority.

The design of the Tyet is unmistakable. It consists of a loop of cloth, tied in a knot, with two sashes hanging down below the loop on either side. In this respect it closely resembles the ankh, the Egyptian hieroglyph for life, and some scholars believe the Tyet was originally a variant of the ankh, its arms bent downward to distinguish it from its more famous cousin. Like the ankh, the Tyet sign is often translated as "life" or "welfare," and in representational contexts it appears in the same places: on temple walls, on coffins, on the shrines that housed statues of the gods. But where the ankh is the sign of life in general, the Tyet became the sign of life through blood, through the female body, through the protective magic of the goddess who was mistress of both.

The association with Isis solidified during the New Kingdom, from 1550 to 1070 BCE, perhaps because the Tyet was so frequently paired with the djed pillar, the symbol of Osiris, Isis's murdered husband and the king of the dead. The djed is a pillar with four horizontal bars, representing the backbone of Osiris and the stability of the cosmos, and when the Tyet and the djed appear together, they allude to the divine couple whose love and magic conquered death itself. In this pairing, the djed represents masculine power and the Tyet represents feminine power, the pillar and the knot, the backbone and the womb, the god who was killed and the goddess who brought him back. The two symbols are frequently carved together in decorative bands on temple walls and columns, and they appear together on the sarcophagus of Tutankhamun, the boy king whose tomb preserved so much of New Kingdom art in perfect condition.

The Tyet's most powerful association is with blood, specifically the blood of Isis. The Book of the Dead, Spell 156, gives the classic formula for the amulet: "The blood of Isis, the spells of Isis, the magical words of Isis shall keep this great one strong, and shall protect him from whosoever would harm him, do to him such things as he abominateth." The spell instructs that the amulet be made of red jasper, carnelian, or red glass, materials whose colour matched the blood that the amulet represented. Red glass was particularly precious, as its colour came from the addition of gold to the molten glass, making the amulet not only magically potent but materially valuable. The Metropolitan Museum of Art holds a Tyet amulet of red jasper from Abydos, dating to the New Kingdom, six and a half centimetres high, its loop perfectly carved and its sashes hanging straight, the colour of dried blood preserved in stone for three thousand years.

Yet the Tyet was not always red. Tutankhamun was buried with a beautiful blue Tyet amulet, the colour of Egyptian faience, whose blue represented the renewal of life rather than the blood that sustained it. Other amulets were fashioned from yellow sycamore wood, the tree sacred to Nut, Isis, and Hathor, the great sky goddess who was mother to Isis and grandmother to Horus. These variations suggest that the Tyet's meaning was flexible, that the knot could represent blood or rebirth, death or life, depending on the material and the context in which it was used.

The meaning of the Tyet's shape has been debated for generations. The most widely accepted interpretation is that it represents a knotted piece of cloth, perhaps the girdle or sash that tied the garments of the gods in Egyptian art. Knots were widely used as amulets because the Egyptians believed they bound and released magic, and the Pyramid Texts, the oldest religious texts in the world carved into the walls of the pyramid of Unas at Saqqara around 2400 BCE, record that "Isis and Nephthys work magic on Thee with knotted cords." In this context, the Tyet is a magical knot, a binding that holds the forces of chaos at bay and releases the forces of life into the body of the dead king.

Other interpretations are more specific and more intimate. Some scholars, following the Egyptologist E.A. Wallis Budge, have suggested that the Tyet represents the female reproductive organs, the stylised vulva and womb of Isis in her role as the universal mother. Others have proposed that it depicts the cloth worn by Egyptian women during menstruation, a sanitary cloth or girdle that caught the blood that the Egyptians considered powerfully magical. A still more specific theory holds that the Tyet represents a ritual tampon inserted into the vagina to prevent miscarriage, and that Isis herself used such a device to protect Horus while he was still within her womb, keeping him safe from the serpents and scorpions that her brother Set, the god of chaos and storms, sent against the infant god. Chapter 156 of the Book of the Dead confirms that the fertility of Isis, linked with blood, is intact, and the amulet has been found tucked between the legs of pregnant women in tombs, as if the knot were still performing its protective function in the grave.

The Tyet was not exclusively Isis's. In the Third Intermediate Period and later, the symbol was also associated with Nephthys, Isis's sister and the guardian of the dead, and with Nut, the sky goddess and mother of the divine siblings. In some Late Period statues, the Tyet is personified as a goddess in her own right, the knot forming the shape of a dress with a centre part and side pieces, the garment's stylised belt becoming the body of a deity. These personified Tyets appear in contexts of resurrection and eternal life, the knot transformed from an amulet into a living goddess who protects the dead. In the Graeco-Roman period, the tradition of tying the Knot of Isis into the robes of priestesses spread from Egypt across the Mediterranean, and statues of Isis from Hadrian's villa at Tivoli show the goddess with knots tied into the straps of her clothing, the magical binding visible to every worshipper who approached her shrine.