Trait and situational forgiveness are vital coping mechanisms and stress responses in the face of interpersonal transgressions. The hypothalamic-pituitary-adrenal (HPA) axis plays a key role in regulating these strategies in response to such transgressions. Building on this foundation, Study 1 examined the impact of cumulative genetic effects of the HPA axis (i.e., a weighted measure of genetic predisposition, calculated by combining the relative contributions of multiple genetic polymorphisms and the number of protective alleles associated with positive psychological traits) on trait forgiveness (N = 852). Study 2 investigated the relationship between these genetic effects, cortisol reactivity, and forgiveness responses following romantic partner conflict (N = 200). Results from Study 1 revealed that higher cumulative genetic scores were associated with stronger trait forgiveness. Study 2 showed that individuals with the higher cumulative genetic scores exhibited more forgiveness responses toward their partners after conflict. Moreover, participants who experienced stronger negative emotions and greater cortisol reactivity were more likely to exhibit forgiveness responses toward their partners. These findings highlight the biological mechanisms underlying forgiveness, emphasizing how genetic and physiological factors of the HPA axis shape adaptive interpersonal coping strategies.