BACKGROUND Neurodegenerative diseases and spinal cord injury can affect respiratory function often through motor neuron loss innervating the diaphragm. To reinnervate this muscle, new motor neurons could be transplanted into the phrenic nerve (PN), allowing them to extend axons to the diaphragm. These neurons could then be driven by an optogenetics approach to regulate breathing. This type of approach has already been demonstrated in the peripheral nerves of mice. However, there is no established thoracoscopic approach to PN injection. Also, there is currently a lack of preclinical large animal models of diaphragmatic dysfunction in order to evaluate the efficacy of potential treatments. OBJECTIVE To evaluate the feasibility of thoracoscopic drug delivery into the PN and to assess the viability of hemidiaphragmatic paralysis in a porcine model. METHODS Two Landrace farm pigs underwent a novel procedure for thoracoscopic PN injections, including 1 nonsurvival and 1 survival surgery. Nonsurvival surgery involved bilateral PN injections and ligation. Survival surgery included a right PN injection and transection proximal to the injection site to induce hemidiaphragmatic paralysis. RESULTS PN injections were successfully performed in both procedures. The animal that underwent survival surgery recovered postoperatively with an established right hemidiaphragmatic paralysis. Over the 5-d postoperative period, the animal displayed stable vital signs and oxygenation saturation on room air with voluntary breathing. CONCLUSION Thoracoscopic targeting of the porcine PN is a feasible approach to administer therapeutic agents. A swine model of hemidiaphragmatic paralysis induced by unilateral PN ligation or transection may be potentially used to study diaphragmatic reinnervation following delivery of therapeutics.