ObjectivesWe assessed the impact of the COVID-19 pandemic on social determinants of health, mental health, substance use, and access to mental health and harm reduction services among key populations disproportionately impacted by sexually transmitted and blood-borne infections (STBBI).MethodsOnline surveys (2021‒2022) were conducted in Canada among people who use drugs or alcohol (PWUD); African, Caribbean, and Black people (ACB); and First Nations, Inuit, and Métis peoples (FNIM). Descriptive analyses were conducted on social determinants of health, substance use, and access to services, stratified by changes in mental health status since the start of the pandemic.ResultsA total of 3773 participants (1034 PWUD, 1556 ACB, and 1183 FNIM) completed the surveys, with 45.6% reporting a major/moderate impact of the pandemic on their ability to pay bills and 53% experiencing food insecurity since the start of the pandemic. Half (49.4%) of participants reported deteriorating mental health. A higher increase in substance use and related behaviours was seen in those with worsening mental health. Among those using substances, two thirds (69.4%) of those with worsening mental health reported increasing their use of substances alone, compared to 46.9% of those with better/similar mental health. Access to mental health and harm reduction services was low.ConclusionThese intersecting health issues are among the risk factors for STBBI acquisition and act as barriers to care. Equitable interventions and policies addressing downstream and upstream determinants of health, with meaningful and sustainable leadership from key populations, may improve their health and well-being, to lower STBBI impact and improve future pandemic responses.