Connections between substance use, impairment, and road safety have been frequently researched. Yet, little is known about how simultaneous use of opioids and alcohol affects road safety outcomes, which is an increasingly critical link within the current landscape of the substance use environment and public health. Lack of this understanding is partly due to testing complications and data limitations. We define polysubstance use here as alcohol and opioids consumed together or within a small-time window such that both are present in the system. This polysubstance use is on the rise and produces greater health risks than when the substances are consumed separately. Given the increasing rate of opioid use, high prevalence of alcohol use, and dangers of polysubstance use, we aim to synthesize literature on the prevalence and impact of this polysubstance on road safety-related outcomes. We performed a systematic review of studies published between 1974 and 2020 that examined opioid and alcohol use exposures and road safety-related outcomes. Out of 644 initial findings, 20 studies were included in this review. Outcomes included motor vehicle crash injuries, deaths, or driver culpability; suspected driving under the influence; and simulated driving performance. Evidence from multiple sources showed a significant rise, approximately 1% to 7%, in the prevalence of opioids among fatally injured drivers in the U.S. from 1995 to 2016. Information published on the simultaneous presence of opioids and alcohol in people involved in crashes was scarce. The limited available findings point toward an overlap where up to 30% of opioid-positive people involved in a crash were also positive for alcohol. Studies also suggest a possibly elevated risk presented by this polysubstance use relative to the substances used alone, though the majority of identified studies did not estimate this association. The synthesized research indicates that alcohol and opioid use is not uncommon and may be increasing among people involved in adverse driving events. More research and better data are needed to improve estimates of association with road traffic-related outcomes, potentially improving substance testing in current surveillance systems or using linked data sets and other novel data sources to improve estimates.