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Purpose The impact of emergency department (ED) visits related to opioid and psychotropic substances has become increasingly critical in the context of the COVID-19 pandemic. This study evaluates whether the COVID-19 lockdown was temporally associated with an increasing trend of opioid- and psychotropic-related ED visits in Saudi Arabia.Methods An interrupted time series analysis was conducted using data on ED visits from a centralised Saudi electronic health records database (1 February 2018–30 April 2022). Additionally, laboratory tests related to substance abuse/misuse were obtained from a centralised Saudi toxicology database (1 January 2019–31 May 2021). Adults (≥18 years) with ED visits related to opioid use disorders (OUDs) or psychotropic misuse were included. The immediate (pulse) and prolonged (slope) effects temporally associated with the March 2020 COVID-19 lockdown on substance abuse-related ED visits were evaluated using autoregressive integrated moving average models.Results 3730 ED visits and 390 toxicology tests related to OUDs and 517 ED visits and 3513 toxicology tests related to psychotropic misuse were identified. The lockdown was temporarily associated with an immediate increase in OUD-related ED visits (pulse: 14.75 visits, 95% CI 9.65 to 19.86), followed by a monthly decrease (slope: −0.06 visits, 95% CI −0.08 to −0.03). It was also temporally associated with an immediate decrease in psychotropic-related ED tests (pulse: −185.7, 95% CI −309.50 to −61.99).Conclusions The COVID-19 lockdown was temporally associated with changes in both OUD-related ED visits and psychotropic ED tests. These findings underscore the need for policies to mitigate substance use risks during such interventions and to improve data quality for future research.