The lesser peachtree borer, Synanthedon pictipes (Grote & Robinson) (Lepidoptera: Sesiidae), is indigenous to eastern North America. It is a pest of commercially grown Prunus spp., especially to southeastern peach orchards where earlier regulatory changes affected pesticide use on peach leading to increased S. pictipes damage. Pest management practices are now having a positive effect toward control of this pest, but cost-competitive biological control solutions that promote environmental stewardship are needed. Here, we tested four Steinernema species and five Heterorhabditis species of entomopathogenic nematodes against larval S. pictipes. Included were four strains of S. carpocapsae (All, DD136, Sal, and Hybrid2) and three strains of S. riobrave (3–8b, 7–12, and 355). Larvae treated with any strain of S. carpocapsae always resulted in <20% survival, whereas larval survival was always >50% when treated with any other Steinernema or Heterorhabditis spp. These differences were always significant for the Hybrid2 strain of S. carpocapsae and similarly for other tested S. carpocapsae strains except for when larvae were treated with the 3–8b strain of S. riobrave. In addition, we determined the susceptibility of different size S. pictipes larvae, because they occur simultaneously in orchards, and we found that larvae rated as “medium” and “large” were significantly more susceptible than “small” larvae. Last, we demonstrated that moisture-retaining covers (placed over S. pictipes-infested wounds on peach limbs) increased efficacy of nematode treatments against larval S. pictipes. Even when using highly virulent nematodes against S. pictipes, it is likely that an aboveground application will require an environmental modification to remain efficacious.