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People with HIV (PWH) with a history of cancer are more likely to experience poor psychosocial well-being compared to those without HIV. This study aims to assess the associations between social and healthcare disruptions due to the COVID-19 pandemic with psychosocial well-being among cancer survivors with and without HIV. A cross-sectional survey was conducted between April and September 2020 among participants of the MACS/WIHS Combined Cohort Study with a history of cancer. The primary exposures were social disruptions (loss of job, child care, financial support, housing, and health insurance) and healthcare disruptions (unable to attend a healthcare appointment, obtain medications, and afford medical care). Psychosocial outcomes included depressive symptoms, anxiety symptoms, stress, loneliness, social support, social support satisfaction, and resilient coping. We estimated adjusted prevalence ratios (aPRs) with 95% confidence intervals (95% CIs) using multivariable Poisson regression. Cancer survivors (N = 452) included 63.7% PWH and 51.5% men. Overall, PWH were more likely to experience social disruptions compared to those without HIV (49.6% vs. 36.6%; p = 0.008). Among cancer survivors with HIV, two or more social disruptions were associated with high depressive symptoms (aPR = 2.19, 95% CI = 1.56, 3.08), anxiety symptoms (aPR = 2.36, 95% CI = 1.25, 4.48), stress (aPR = 3.32, 95% CI = 1.25, 8.79), and loneliness (aPR = 2.16, 95% CI = 1.25, 3.74), and one or more healthcare disruptions were associated with high depressive symptoms (aPR = 1.53, 95% CI = 1.22, 1.94), stress (aPR = 2.92, 95% CI = 1.53, 5.58), loneliness (aPR = 1.78, 95% CI = 1.23, 2.57), and low social support (aPR = 1.75, 95% CI = 1.08, 2.82). Disruptions were associated with poorer mental health among PWH but not among people without HIV.