The aim of this study was to examine the effects of hangover on mood, multitasking ability, and psychological stress reactivity to cognitive demand. Using a crossover design and semi-naturalistic methodology, 25 participants attended the laboratory in the morning following a night of (i) alcohol abstinence and (ii) alcohol self-administration during a typical night out (with order counterbalanced across participants). They completed a four-module multitasking framework (MTF, a widely used laboratory stressor) and a battery of questionnaires assessing mood, hangover symptom severity, and previous night’s sleep. The effects of the MTF on mood and perceived workload were also assessed. Participants in the hangover condition reported significantly lower alertness and contentment coupled with a higher mental fatigue and anxiety. Multitasking ability was also significantly impaired in the hangover condition. Completion of the cognitive stressor increased reported levels of mental demand, effort, and frustration, and decreased perceived level of performance. MTF completion did not differentially affect mood. Lastly, participants rated their sleep as significantly worse during the night prior to the hangover compared with the control condition. These findings confirm the negative cognitive and mood effects of hangover on mood. They also demonstrate that hangover is associated with greater perceived effort during task performance.