COVID-19 emerged at a time when many countries were already struggling with an escalating opioid crisis and increasingly complex patterns of polysubstance abuse. Although global attention focused on the spread of the virus, individuals with substance use disorders faced major disruptions in care, unstable drug supplies, and heightened socioeconomic pressures. This narrative review synthesizes peer-reviewed literature published through 2021 to examine how the pandemic affected overdose mortality, patterns of polysubstance use, and access to services across diverse settings. Evidence from epidemiological studies, clinical research, and qualitative reports shows that fatal overdoses increased during the pandemic, driven by treatment disruptions, isolation, changes in drug availability, and emotional distress. Polysubstance involvement, including combinations of opioids, stimulants, and sedatives, played a significant role. While telehealth expansion and more flexible medication policies helped sustain treatment for some, these adaptations were unevenly implemented and did not fully reach structurally disadvantaged groups. The findings underscore the necessity for robust public health strategies that guarantee continuity of treatment, safeguard harm reduction programs, and mitigate socioeconomic inequities during future emergencies.