The current study aimed to understand motivations of high-risk polysubstance use. Semi-structured interviews were conducted in New York City with 20 individuals with frequent recent polysubstance use. Two analysts coded the interviews (κ = 93.97). Five themes related to motivation for polysubstance use were found: (1) balance, prolong, or enhance effects, (2) self-medicate physical ailments, (3) cope with emotional distress, (4) drug-induced cravings, and (5) responding to social contexts. Individuals reported simultaneous or sequential co-use to balance, prolong or enhance a ‘high’ (theme 1). Participants engaged in polysubstance use to alleviate withdrawal symptoms, to induce sleep and self-medicate physical pain (theme 2) and to provide relief from emotional distress (theme 3). Other themes included drug-induced cravings (theme 4) and responding to social contexts (theme 5) including both social situations and economic availability. Motivations for polysubstance use may provide important insight into harm reduction and treatment settings solutions.