The health and economic threats posed by the COVID-19 pandemic can be sources of great distress among people living with HIV, which in turn can impact the management of their HIV disease. We examined change in depression from pre- to post-lockdown restrictions and correlates of elevated depressive symptoms, including antiretroviral therapy (ART) adherence. Participants enrolled in a randomized controlled trial of an ART adherence intervention in Uganda. The month-12 follow-up assessment was fully administered just prior to the start of the pandemic-related lockdown in March 2020; at the conclusion of the lockdown three months later, we administered a mixed-methods phone-based assessment. ART adherence was electronically monitored throughout the study period, including during and after the lockdown. Depression was assessed with the 8-item Patient health questionnaire (PHQ-8), on which scores > 9 signify a positive screen for elevated depressive symptoms. A sample of 280 participants completed both the month-12 and post-lockdown assessments. Rates of elevated depressive symptoms nearly tripled from month 12 (n = 17, 6.1%) to the post-lockdown assessment (n = 50, 17.9%; McNemar test <.001). Elevated depressive symptoms at post-lockdown were associated with being female, indicators of economic struggles at month 12 (unemployment, low income, high food insecurity), and lower ART adherence during the 3-month lockdown period [mean of 71.9% (SD = 27.9) vs. 80.8% (SD = 24.1) among those not depressed; p =.041] in bivariate analysis. In multiple regression analysis, higher food insecurity [adj. OR (95% CI) = 4.64 (2.16–9.96)] and perception that the pandemic negatively impacted ART adherence [adj. OR (95% CI) = 1.96 (1.22–3.16)] remained associated with a greater likelihood of elevated depressive symptoms, when other correlates were controlled for. Qualitative data suggested that economic stressors (lack of food, work, and money) were key contributors to elevated depressive symptoms, and these stressors led to missed ART doses because of lack of food and stress induced forgetfulness. Elevated depressive symptoms significantly increased during the COVID-19 lockdown and was associated with food insecurity and reduced ART adherence. Mechanisms for identifying and treating depression and food insecurity are needed to help PLHIV cope with and mitigate the harmful effects of unexpected crises that may impede disease management and access to food.