Measuring drug use behaviors in individuals and across large communities presents substantial challenges, often complicated by socioeconomic and demographic variables. To detect spatial and temporal changes in community drug use by analyzing concentrations of analytes in influent wastewater and exploring their associations with area-based socioeconomic and sociodemographic metrics like the area deprivation index (ADI) and rural-urban commuting area (RUCA) codes. This longitudinal, cross-sectional wastewater study was performed from May 2022 to April 2023 and included biweekly influent wastewater samples of 39 analytes from 8 sampling locations across 6 wastewater treatment plants in southern Nevada. Statistical analyses were conducted in December 2023. It was hypothesized that wastewater monitoring of pharmaceuticals and personal care products (PPCPs) and high-risk substances (HRSs) could reveal true spatial and temporal drug use patterns in near-real time. Data collection of samples for PPCPs and HRSs was performed using mass spectrometry. Both ADI and RUCA scores were utilized to characterize neighborhood contexts in the analysis. The false discovery rate (FDR) method was utilized to correct for multiple comparisons (PFDR). Over the 12-month wastewater monitoring period, 208 samples for PPCPs and HRSs were collected, and analysis revealed an increase in the consumption of HRSs and the seasonal variation in PPCP use in southern Nevada. There was a significant increase in levels of stimulant-associated analytes, such as cocaine (β = 9.17 × 10-4; SE = 1.29 × 10-4; PFDR = 1.40 × 10-10), and opioids or their metabolites, notably norfentanyl (β = 1.48 × 10-4; SE = 1.88 × 10-4; PFDR = 1.66 × 10-12). In contrast, DEET, an active ingredient in mosquito and tick repellents, demonstrated a seasonal use pattern (β = -4.85 × 10-4; SE = 2.09 × 10-4; PFDR = 4.87 × 10-2). Wastewater from more disadvantaged or rural neighborhoods, as assessed through ADI and RUCA scores, was more likely to show a significant positive correlation with HRSs, such as cocaine (β = 0.075; SE = 0.038; P = .05) and norfentanyl (β = 0.004; SE = 0.001; P = 1.64 × 10-5). These findings suggest that wastewater monitoring of PPCPs and HRSs offers a complementary method to existing public health tools, providing timely data for tracking substance use behaviors and use of PPCPs at a population level.