Background <p>Involvement with psychoactive substances among emerging adults varies considerably in its frequency, severity, and co-occurrence. Person-centred approaches, which identify groups of individuals with shared patterns of substance involvement, may provide a more nuanced understanding of psychosocial risk than traditional substance-specific analyses. This study aimed to identify distinct substance involvement profiles among Colombian university students and examine differences in depression, anxiety, and suicide risk across these profiles, as well as sociodemographic predictors of profile membership.</p> Methods <p>A cross-sectional multicentre study was conducted with 1,491 university students aged 18–26 years from the four largest cities of Colombia. Self-reported substance involvement across tobacco, alcohol, cannabis, cocaine, amphetamines, and sedatives was assessed. A two-step clustering approach using hierarchical and k-means cluster analyses was employed to identify substance involvement profiles. Differences in depression, anxiety, and suicide risk across profiles were examined using one-way analyses of variance, and multinomial logistic regression was used to identify sociodemographic predictors of profile membership.</p> Results <p>A three-cluster solution identified low- (80.5%), moderate- (14.6%), and high-involvement (4.9%) profiles. Profiles differed significantly in depression (<i>F</i> = 6.99, <i>p</i> = 0.001), anxiety (<i>F</i> = 5.51, <i>p</i> = 0.004), and suicide risk (<i>F</i> = 6.49, <i>p</i> = 0.002), with moderate- and high-involvement profiles reporting higher levels of depression, anxiety, and suicide risk. Men (OR = 1.64, <i>p</i> = 0.002) and students from higher socioeconomic backgrounds (OR = 2.45–2.83, <i>p</i> ≤ 0.001) were more likely to belong to the moderate- profile, while students from the Central region showed greater odds of membership in both the moderate- and high-involvement profiles than those from other regions (OR = 2.49–2.57, <i>p</i> ≤ 0.009).</p> Conclusions <p>Distinct substance involvement profiles among Colombian university students were associated with meaningful differences in mental health outcomes. High involvement with cocaine, amphetamines, and sedatives may represent useful indicators of risk for poorer mental health outcomes and provide opportunities for earlier screening and intervention. These findings support integrated approaches to substance use and mental health assessment, alongside more targeted prevention efforts among young adults.</p>