Abstract Introduction We draw on activity theory of concepts to examine ‘meaning of occupation’ and ‘substance use’ beyond preconceived notions of inherent positive or negative experiences. Objective To explore nuanced meanings of substance use and associated occupations. Method An online survey and semi-structured interviews were used to collect data from professionals about prevalence of substance use, substance effects, and personal experiences. In analyzing the interview data, we attended to substance use as a discrete occupation in itself, substance use co-occurring with other occupations, and substance use altering the performance, participation, and experience of occupations. Results Three broad themes related to meaning: i) complex meanings attributed to substance use, ii) meanings of substance use as shifting and variable, and iii) meanings of substance use in the context of other occupations. Substance use enhances occupations, transforms meaning of occupations, and mitigates less desired aspects of occupations. Work, construed as positively meaningful and valued in occupational therapy literature, was a source of stress, unhappiness, and worry; substance use facilitated relaxation and pleasure. Conclusion This study furthers occupational therapy knowledge with respect to implications for conceptualization that extend beyond dualist framings and implications for occupational therapy education, practice, and policy.