The series antagonist, played by Joseph Morgan, was seemingly defeated in the season three finale, but returned in the body of Tyler (Michael Trevino).
However, Plec explained that Klaus will encounter many dangers in Mystic Falls, which he will not be able to defeat with a hybrid army now that Elena (Nina Dobrev) is a vampire.
"The loss of the doppelganger is gonna be a [big deal] for Klaus and will drive his actions for the season," TV Guide quotes her as saying. "Suddenly he's vulnerable for many reasons.
"There's a stake that can kill him, a witch that can desiccate him (Bonnie), and no way to build up the hybrid army he needs - psychologically, at least - to feel safe."
Plec added that Klaus may also be targeted by Caroline (Candice Accola), who was about to run away with Tyler in the finale.
"Caroline's going to be peeved at him once she realises he bamboozled her," the showrunner said. "In other words, he ain't gonna be so happy."
Plec recently said that she expects Morgan to return to Vampire Diaries.
She hinted: "I'd say there's a fairly significant chance, if not a 99.9% likelihood that body did not burn up in that coffin."