Abstract Objective Numerous studies have illustrated the importance of social determinants of health (SDH) on neuropsychological outcomes (Zuelsdorff, 2020); however, what moderates this relationship is poorly understood. One factor that negatively affects neuropsychological outcomes is substance use (Volkow et al., 2016). This study, the first to our knowledge, examines the intersection between a composite measure of SDH, the Area Deprivation Index (ADI; Kind et al., 2018), and current substance use (CSU). We hypothesized that CSU would moderate SDH’s effect on neuropsychological test performance. Method This sample is 236 diverse adults (M age = 55; 64% female; 44% White) who completed a neuropsychological examination in an outpatient neuropsychology clinic between 2017–2023. The composite measure of SDH was the ADI (Kind et al., 2018), which uses 17 socioeconomic indicators. Test scores were converted to z-scores for six cognitive domains (processing speed, attention, executive functioning, language, visuospatial abilities, and memory) and a global cognitive function score. CSU was self-reported use of tobacco, alcohol, and marijuana. Regressions were used to test the hypothesized interaction. Results Results partially supported CSU’s moderation of ADI and cognition. CSU only moderated the relationship between ADI and memory functioning (b = −0.08,p = 0.008); the indirect association between ADI and memory ability was stronger for those who endorsed CSU, even after controlling for covariates. Conclusions Findings demonstrate the interaction between CSU and ADI in predicting memory abilities. Analyses suggest using substances compounds the detrimental effects of neighborhood deprivation on memory, independent of demographic factors. Such results underscore the importance of considering socioecological factors in neuropsychological evaluations and test development.