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Background: Methamphetamine (MA) use in people living with HIV (PLWH) has been linked to neurocognitive and behavioral dysregulation. We hypothesized that PLWH with active MA use (MAHIV) would show poorer cognitive performance, greater emotional and sleep burden, higher behavioral risk, and alterations in circulating biomarkers of immune activation and neuronal injury, relative to PLWH without MA use and HIV-negative Controls. Methods: Cross-sectional analytic study of 121 adults: PLWH with MA use (MAHIV, n = 40), PLWH without use (n = 42), and HIV-negative Controls (n = 39). Outcomes were ART discontinuation, physical activity, neurocognition (MoCA), depression (BDI), anxiety (GAD-7), sleep (PSQI), and substance use (ASSIST). Circulating biomarkers measured by ELISA: sCD14, neuron-specific enolase (NSE), S100B, and neurofilament light chain (NfL). Results: MAHIV participants had more frequent ART discontinuation than PLWH and the lowest physical activity. Chemsex with polysubstance use, condomless sex, and multiple partners were most prevalent in MAHIV. This group showed the highest anxiety and depressive burdens, and the greatest sleep disturbances. Global cognition (MoCA) was lowest in MAHIV, with significant deficits in executive function, memory, attention, and language; 82.5% had at least mild cognitive impairment. sCD14 was significantly higher in MAHIV than in PLWH and Controls, and NSE was elevated in both MAHIV and PLWH versus Controls. sCD14 correlated inversely with MoCA and positively with GAD-7 and BDI-II. Conclusions: Among PLWH, MA use is associated with greater ART nonadherence, syndemic mental-health and sleep disturbances, broader neurocognitive deficits, and elevations in circulating sCD14 and NSE. The sCD14-cognition and sCD14-mood relationships highlight chronic immune activation as a candidate pathway for neurocognitive and affective impairment and support sCD14 and NSE as potential stratification and monitoring biomarkers in MA-using PLWH.