Prenatal exposure to nicotine and cannabis can adversely affect fetal development, posing a serious public health issue. Importantly, pregnant women report using these drugs simultaneously, although the effects of simultaneous exposure on the offspring remains unknown. Moreover, these substances are increasingly consumed via e-cigarette, but there are limited studies examining outcomes of such exposure. Thus, this study used a rodent model to investigate the effects of prenatal exposure to nicotine, tetrahydrocannabinol (THC; main psychoactive component in cannabis), or the combination via e-cigarette on cognitive function. From gestational days 5-20, pregnant rats were exposed to nicotine (36 mg/mL), THC (100 mg/mL), a combination, or vehicle via e-cigarette vapor inhalation. Behavior was measured among the offspring, using a 2 (Nicotine, Vehicle) x 2 (THC, Vehicle) x 2 (female male) design, with 11-14 subjects per treatment group. On postnatal day (PD) 55-60, offspring were tested on a working memory version of the Morris Water Maze visuospatial task, where subjects locate a hidden platform submerged in a water tank by using extramaze spatial cues. Each session comprised a training trial where the platform location was randomly assigned, followed by a testing trial to measure spatial memory. The platform location changed each session, requiring subjects to learn a new location each time and taxing working memory. A 0-second intertrial interval (ITI) occurred between training and testing trials from PD 55-57 and a 60-second ITI from PD 58-60. Prenatal nicotine exposure, alone or in combination, impaired working memory in males, but not females. In contrast, prenatal THC exposure alone impaired working memory in both males and females, but only during the 0-sec ITI. Interestingly THC, alone or in combination, increased anxiety-like behavior in females. Thus, prenatal exposure to these drugs via e-cigarette may alter both cognitive and emotional development in a sex-dependent manner. Importantly, these data illustrate the potential risks of e-cigarette use during pregnancy, findings with important implications for pregnant women and for informing public policy.