<p><b>Objective:</b> To determine the prevalence of drug-related problems and the factors influencing them among adult psychiatric inpatients.</p><p><b>Methods:</b> A multi-centre cross-sectional observational study was conducted from April to July 2021 at five randomly selected hospitals in Northwest Ethiopia. A total of 325 consecutively sampled patients participated in the study. Clinical pharmacists assessed the drug-related problems based on clinical judgement supported by updated evidence-based disease guidelines. We used the Medscape drug-interactions checker to check drug-to-drug interactions. The results were summarised using descriptive statistics, including frequency, mean, and standard deviation. For each variable, an odds ratio with a 95% confidence interval was calculated, as well as the related p-value. The value of <i>p</i> ≤ 0.05 was considered statistically significant.<p><b>Results:</b>From the total number of 325 study participants, more than half of them (52.9%) were females, and the mean age±(standard deviation) was 30.8±11.3years. At least one drug-related problem was recorded by 60.9% to 95% confidence interval (55.7–65.8) of study participants, with a mean of 0.6±0.49 per patient. Additional drug therapy was the most common drug-related problem (22.8%) followed by non-adherence to medicine (20.6%) and adverse drug reactions (11%), respectively. Factors independent associated with drug-related problems were rural residence (adjusted odds ratio=1.96, 95% confidence interval: 1.01–2.84, p-value=0.046), self-employed (adjusted odds ratio=6.0, 95% confidence interval: 1.0– 36.9, <i>p</i>-value=0.035) and alcohol drinkers (adjusted odds ratio=6.40, 95% confidence interval: 1.12–37.5, p-value=0.034).<p><b>Conclusion:</b> The prevalence of drug-related problems among adult psychiatric patients admitted to psychiatric wards was high. Healthcare providers give more attention to tackling these problems. Being a rural resident, self-employed, and alcohol drinkers were associated with drug-related problems.</p>