Apparatus and methods for transient overstress protection with false condition shutdown are provided herein. In certain configurations, a high-voltage tolerant actively-controlled protection circuit includes a transient overstress detection circuit, a clamp circuit electrically connected between a first node and a second node, a bias circuit that biases the clamp circuit, and a false condition shutdown circuit. The transient overstress detection circuit generates a detection signal indicating whether or not a transient overstress event is detected between the first and second nodes. Additionally, the false condition shutdown circuit generates a false condition shutdown signal based on low pass filtering a voltage difference between the first and second nodes, thereby determining independently whether or not power is present. The bias circuit controls operation of the clamp circuit in an on state or an off state based on the detection signal and the false condition shutdown signal.