Chronic administration of nicotine or exposure to stress can produce long-lasting behavioral and physiological changes in humans and animals alike. Further, the impact of nicotine and stress exposure can be inherited by offspring to produce persistent changes in physiology and behavior. To determine if nicotine and stress interact across generations to influence offspring behavior we exposed F0 male mice to nicotine and F1 male and female mice to chronic unpredictable stress during adolescence. We then measured locomotor sensitization to repeated nicotine injections in the subsequent F2 and F3 generations. Stress exposure alone (F1) did not influence locomotor sensitization in any lineage. However, in the F1 male lineage, F0 nicotine exposure abrogated locomotor sensitization in F2 male and transiently enhanced locomotor sensitization in F2 female offspring. These effects were not passed down to the F3 generations or observed in the F1 female lineage. F1 stress exposure modulated the effects of prior F0 nicotine exposure in a sex-dependent manner. Specifically, stress blunted the nicotine-induced enhancement in locomotor sensitization observed in F2 female offspring of F1 males. The effect of F0 nicotine and F1 stress exposure in females appears to have skipped a generation and enhanced nicotine sensitization only in the F3 generation, and only in females. This novel multigenerational exposure paradigm examining the inheritance of two different environmental exposures demonstrates that nicotine responses can be modified by nicotine and stress exposure from previous generations, and these effects are strongly influenced by sex.