The present disclosure provides electroporation systems and methods of preconditioning tissue for electroporation therapy. An electroporation generator includes an electroporation circuit, a preconditioning circuit, and a controller. The electroporation circuit is configured to be coupled to a catheter for delivering the electroporation therapy to target tissue of the patient. The electroporation circuit is further configured to transmit an electroporation signal through the catheter. The preconditioning circuit is configured to be coupled to a preconditioning electrode for stimulating skeletal muscle tissue of the patient. The preconditioning circuit is further configured to transmit a preconditioning signal to the preconditioning electrode. The controller is coupled to the electroporation circuit and the preconditioning circuit, and is configured to synchronize transmissions of the electroporation signal and the preconditioning signal such that the preconditioning signal is transmitted prior to transmission of the electroporation signal.