The aim of this study was to identify the sociodemographic factors associated with emotional distress and determine if the quality of family relationships and the perception of social isolation can protect those who transacted sex or used psychoactive substances from emotional distress during the COVID-19 pandemic. Data for 426 people who transacted sex and 630 persons who used psychoactive drugs during the COVID-19 pandemic were extracted from a database of participants recruited from 152 countries. The extracted data were the dependent (emotional distress), independent (age, sex, education status, employment status, HIV status, the perception of social isolation, and the quality of family relationships), and confounding (country income level) variables. Multivariable logistic regression analyses were conducted to determine the associations between the dependent and independent variables after adjusting for confounders. Students who transacted sex (AOR:2.800) and who used psychoactive substances (AOR:2.270) had significantly higher odds of emotional distress. Participants who transacted sex, lived with HIV (AOR:2.582), or had the same/better quality of family relationships (AOR:1.829) had significantly higher odds of emotional distress. The participants who used psychoactive substances, had tertiary education (AOR:1.979), were retired (AOR:2.772), were unemployed (AOR:2.263), or felt socially isolated (AOR:2.069) had significantly higher odds of emotional distress. Being a student was the only sociodemographic risk indicator common to both populations. The risk indicators and protective factors for emotional distress differed for both populations despite both being at high risk for emotional distress.