Background Although substance use has been linked to both suicidal ideation and suicide attempts, the factors underlying these relations remain unclear. The Interpersonal-Psychological Theory of Suicide (ITS) provides a framework for understanding how substance use may increase suicide risk. The purpose of the current study was to examine if frequency of substance use is indirectly related to suicidal ideation and suicide attempts through core ITS variables (i.e., burdensomeness, thwarted belongingness, and suicide capability). Methods An online sample of Mechanical Turk workers (N = 365) completed measures assessing substance use frequency, burdensomeness, thwarted belongingness, suicide capability, suicidal ideation, and suicide attempts. Results After controlling for relevant clinical and demographic covariates, substance use frequency was indirectly related to suicidal ideation through burdensomeness but not thwarted belongingness. Substance use frequency was indirectly related to suicide attempts through suicide capability only. Limitations The cross-sectional design precludes conclusions about the precise nature and direction of the relations examined. The use of a community sample limits generalizability to more severe substance using samples. Conclusions Results highlight the relevance of distinct ITS factors in the relation between substance use frequency and both suicidal ideation and suicide attempts. Results may inform specific targets for novel interventions aimed at reducing suicide risk among substance-using individuals.