This study sought to characterize changes in depressive symptom severity during the COVID-19 pandemic and the association of these changes with HIV viral nonsuppression among people with HIV (PWH). A clinical cohort study. We included PWH in the Johns Hopkins HIV Clinical Cohort who completed the Patient Health Questionnaire 8 (PHQ-8) prepandemic (1 March 2018 to 28 February 2020) and during the COVID-era (1 September 2020 to 28 February 2022). PWH were classified according to depression severity categories prepandemic and during the COVID-era as: consistently depressed (prepandemic PHQ-8 >4 and no change in severity category); consistently nondepressed (prepandemic PHQ-8 ≤4 and no change in severity category); worsened (changed to a higher severity category) and; improved (change to a lower severity category). The association between changes in depressive symptom severity and viral nonsuppression (HIV RNA >200 copies/ml on the earliest viral load measured 7 days before to 12 months after the COVID-era PHQ-8 survey) was assessed using multivariable logistic regression. Of 793 PWH, mean age was 56 (SD 10) years, 60% were male individuals and 88% were Black. After the onset of the pandemic, 60% were consistently nondepressed, 9% were consistently depressed, 15% worsened and 16% improved. PWH who worsened had 2.47 times the odds of viral nonsuppression (95% CI: 1.09-5.55) compared with the nondepressed group. Associations among other groups were not statistically significant. Worsening depression during the COVID-era was associated with HIV viral nonsuppression. Strategies to monitor and address depression among PWH may contribute to reduced risk of viral nonsuppression.