In Graduation, Katherine initiated a violent fight with Elena, believing that Elena got the life that Katherine deserved.
Just as she was about to rip her descendant's heart out of her chest, Elena forced the cure down Katherine's throat, which resulted in Katherine returning to a human/Traveler for the first time in over 500 years.
Klaus was so infuriated with Katherine's sabotage, that she was forced to live on the run for over 500 years as he hunted her down.
Her activities during her first centuries as a vampire are unknown, but at some point between the 15th and 19th centuries, she took on the alias "Katherine Pierce" (an anglicized version of her birth name) and eventually met and befriended Pearl, Anna, and Emily Bennett.
Silas later revealed to Damon that Katherine's blood became the cure after she had ingested it, which is why he wanted Katherine so he could cure himself and die so he could be reunited with his true love in the afterlife.
She ran from him for weeks, but eventually, Damon helped Silas lure Katherine to the house and fed him her blood, which turned him back into a witch.
When the Founder's Council found out the identities of the vampires in town, she faked her death and escaped being sealed in the tomb with the aid of George Lockwood, who helped her in exchange for the moonstone.
During the twentieth century, she continued to keep tabs on Stefan while still hiding from Klaus, including two separate sightings in Chicago in the 1920s and the 1980s.
After failing to induce Klaus' forgiveness by securing the cure and handing it over to Elijah in Season Four, Katherine managed to draw Klaus away from Mystic Falls by revealing to him in a letter that a witch in New Orleans named Jane-Anne Deveraux was plotting against him.
Once Klaus and Elijah officially returned to New Orleans, Katherine moved back to Mystic Falls, confident that the Mikaelsons would be too preoccupied with their complications there to pay any attention to her.
In the late 19th century, she traveled to Mystic Falls, where she met Stefan and Damon Salvatore, whose family hosted her at the Salvatore Estate.