Abstract Introduction A large body of literature indicates that nicotine results in an acute mood “boost,” including increased positive affect and decreased negative affect. Young adults frequently engage in polysubstance use of cigarettes with cannabis and alcohol—a trend that is likely to accelerate with the expanding legalization of cannabis. However, little is known about whether polysubstance use, defined here as combustible tobacco cigarette use within the same hour as cannabis and alcohol, is associated with changes in the nicotine mood boost. The present study aimed to address this gap. Methods Young adults (N = 202, 52% female, mean age = 21 years at time 1) provided ecological moments assessment (EMA) reports of cigarette use over two 7-day bursts spaced 1 year apart. In each report, participants rated mood levels before and after smoking, and indicated cannabis and alcohol use. Mixed-effects location-scale modeling simultaneously tested changes in mood levels and variability related to smoking events with cannabis and/or alcohol compared with smoking-only events. Results From before to after smoking, positive affect increased and negative affect decreased, on average. Overall, the additions of cannabis and/or alcohol had nonsignificant associations with these mean changes. However, polysubstance use, as well as cigarette-cannabis co-use, were each associated with significantly greater within-person variability in the positive and negative affect changes related to smoking. Conclusions The mood benefits associated with smoking were more erratic in the contexts of polysubstance use and cigarette-cannabis co-use. Potential implications for young adults’ long-term nicotine use trajectories are discussed. Implications Among young adults who smoke cigarettes, the mood “boost” from smoking may be more erratic—which is to say, more likely to be either amplified or attenuated—with the additions of cannabis and alcohol together, or cannabis alone. On occasions when young adults seek out cannabis and alcohol to enhance their smoking mood boost, but instead experience a dampening effect, they might consume more nicotine, contributing over time to greater dependence. Future investigation is warranted, with particular attention to nicotine-cannabis co-use.