Abstract Background People who use drugs are at a disproportionately higher risk of mental disorders due to prolonged exposure to psychosocial challenges. However, studies on mental health among people who use drugs in resource-constrained countries are scarce. This study sheds light on the prevalence and correlates of psychological distress among people who use drugs in Cambodia. Methods We conducted this cross-sectional study in the capital city and 11 provinces in 2017. The Respondent Driven Sampling method was adapted to recruit 1677 people who used drugs for face-to-face interviews using a structured questionnaire. Psychological distress was measured using the General Health Questionnaire (GHQ-12). A total score of GHQ-12 > 2 indicated high psychological distress. We performed a multiple logistic regression analysis to identify factors associated with psychological distress. Results We included 1598 participants in the analyses, with a mean age of 28.6 years (SD = 7.8). Of the total, 42% had high psychological distress – 50% in women and 37% in men. The adjusted odds of having high psychological distress were significantly higher among participants who were 25–34 years old and 35 years and above, had been to a drug rehabilitation center, had been insulted by family members, and had been sexually harassed/abused by someone when they were growing up. The odds of having high psychological distress were significantly lower among participants who were male, lived in their own dwelling, reported injecting as the mode of the first drug use, and had someone taking care of them when they got sick. Conclusions This study documents a high prevalence of psychological distress among people who use drugs in Cambodia. Intervention programs that attempt to address mental health problems among people who use drugs in resource-limited settings should be gender- and age-sensitive and target more marginalized subpopulations. Mental health services can be integrated into HIV and harm-reduction programs for people who use drugs.