PurposeMandatory COVID‐19 shelter‐in‐place (SIP) orders have been imposed to fight the pandemic. They may also have led to unintended consequences of increased use of controlled substances especially among rural communities due to increased social isolation. Using the data from the American Association of Poison Control Centers, this study tests the hypothesis that the poison control centers received higher rates of calls related to exposures to controlled substances from rural counties than they did from urban counties during the SIP period.MethodsCall counts received by the poison control centers between October 19, 2019 and July 6, 2020 due to exposure to controlled substance (methamphetamine, opioids, cocaine, benzodiazepines, and other narcotics) were aggregated to per‐county‐per‐month‐per‐10,000 population exposure rates. A falsification test was conducted to reduce the possibility of spurious correlations.FindingsDuring the study period, 2,649 counties in the United States had mandatory SIP orders. The rate of calls reporting exposure to any of the aforementioned controlled substances among the rural counties was higher (14%; P = .047) relative to the urban counties. This overall increase was due to increases in the rates of calls reporting exposure to opioids (26%; P = .017) and methamphetamine (39%; P = .077). Moreover, the rate of calls reporting exposures at home was also higher among the rural counties (14%; P = .069).ConclusionThe mandatory SIP orders may have had an unintended consequence of exacerbating the use of controlled substances at home in rural communities relative to urban communities.