Consequences of drug abuse and addiction affect both men and women, but women tend to rapidly progress through drug addiction phases, have higher drug dependency, and have higher relapse rates. Ovarian hormones fluctuate with female reproductive cycles and are thought to cause increased sensitivity to psychostimulants. Additionally, intermittent social defeat stress induces social avoidance, weight loss, and long-lasting cross-sensitization to psychostimulants, which is associated with increased FosB/ΔFosB expression in the nucleus accumbens (NAc) shell. In this study, we examined the estrous cycle in female rats on social defeat stress-induced amphetamine cross-sensitization through FosB/ΔFosB expression in the NAc shell. Every third day for ten days, we induced social defeat stress in rats through short confrontations with a lactating female resident rat and her pups. In parallel, a group of rats were handled for control. Vaginal swabs were taken daily to assess estrous stage. Ten days after the last stress exposure, rats were administered a low dose of amphetamine (0.5 mg/kg, i.p.), which induced cross-sensitization in stressed rats, evidenced by enhanced locomotor activity. Approximately 3-10 days after amphetamine challenge, brain tissue was collected for immunohistochemistry analyses. Stressed female rats had lower body weight gain, higher social avoidance, and increased FosB/ΔFosB expression in the NAc shell. Differences in FosB/ΔFosB expression in the NAc shell was also observed in handled animals in different estrous stages. Furthermore, rats in proestrous/estrous stages displayed enhanced social defeat stress-induced amphetamine cross-sensitization in comparison to rats in metestrous/diestrous stages. Elucidating the effects of the female reproductive cycle on drug use may provide a novel approach to treatments or therapies in preventing women’s stress-induced vulnerability to substance abuse.