One of the most effective defenses of avian hosts against obligate brood parasites is the ejection of parasitic eggs from the nests. Despite the clear fitness benefits of this behavior, individuals within so-called “egg rejecter” host species still show substantial variation in their propensity to eliminate foreign eggs from the nest. We argue that this variation can be further understood by studying the physiological mechanisms of host responses to brood parasitic egg stimuli: independent lines of research increasingly support the hypothesis that stress-related physiological response to parasitic eggs may trigger egg rejection. The “stress-mediated egg rejection” hypothesis requires that hosts activate the stress-response when responding to parasitic eggs. We tested this prediction by experimentally parasitizing incubating American robins Turdus migratorius, an egg rejecter host to obligate brood parasitic brown-headed cowbirds Molothrus ater, with mimetic or non-mimetic model eggs. To assess the stress response, we measured the heart rate in incubating females immediately after experimental parasitism. We also measured plasma corticosterone and, in a subset of birds, used RNA-sequencing to analyze the expression of proopiomelanocortin (POMC), a precursor of adrenocorticotropic hormone (ACTH), two hours after experimental parasitism. We found that egg type had no effect on heart rate. Two hours following experimental parasitism, plasma corticosterone did not differ between the differently colored model egg treatments or between rejecter and accepter females within the non-mimetic treatment. However, females exposed to non-mimetic eggs showed an upregulation of POMC gene expression in the pituitary compared to females treated with mimetic eggs. Our findings suggest that parasitic eggs may activate the stress-related hypothalamic-pituitary-adrenal axis in an egg-rejecter host species, although the dynamics of this response are not yet understood.