Both inbreeding and herbivory are common in flowering plants, and both are known to reduce fitness. Although inbreeding might also be expected to impact inducible and constitutive plant defenses against herbivores in a variety of ways, investigators have only recently begun to examine the effects of inbreeding on resistance to herbivores. Here, we examined the effects of inbreeding in horsenettle, Solanum carolinense L. (Solanaceae), on herbivore damage and reproductive output under field conditions. In addition, we employed the commercially available Affymetrix tomato (Solanum esculentum L.) microarray to explore changes in S. carolinense gene expression associated with feeding by Manduca sexta) (L.) (Lepidoptera: Sphingidae) caterpillars on inbred and outbred horsenettle plants. We found that the inbred horsenettle plants experienced significantly greater herbivore damage in the field and exhibited only 11% of the seed production of outbred plants. Flea beetles and false potato beetles were the most abundant herbivores observed on the experimental plants, and both were observed significantly more often on inbred plants. The microarray‐generated transcriptomes of horsenettle revealed that the commercially available microarray chips can be reliably used with this important weed, that damage significantly up‐regulates many defense‐related genes, and that inbreeding depresses the expression of many genes especially those located in the jasmonic acid, ethylene, abscisic acid, and systemin‐mediated pathways that regulate the induction of defensive compounds and organic volatiles. Findings of the field study and the gene‐expression analysis are thus complementary, as the former demonstrates that inbreeding impacts plant resistance to herbivores, whereas the latter provides initial insights into the genetic mechanisms underlying these effects and their relationship to fitness.