Lockdown measures enacted in 2020 to control the spread of COVID-19 led to increases in the prevalence of mental health problems. Due to their high-risk status, individuals with chronic diseases may be at increased risk and disproportionately adversely affected by the COVID-19 pandemic. The investigators examined associations between having a high-risk chronic condition, social connectedness, and general distress and COVID-19-specific distress among U.S. adults during the COVID-19 lockdown. Baseline measures of a longitudinal survey collected at the beginning of the pandemic (April to June 2020) were analyzed to identify factors associated with loss of social connectedness from pre- to post-lockdown. The associations between social connectedness and both general and COVID-19-specific psychological distress were adjusted for certain high-risk chronic illnesses and interaction effects. The sample available for analysis included 1354 subjects (262 high-risk chronic diseases and 1092 without chronic illness). Those reporting the loss of social connectedness were younger (median = 39 vs. 42) and more likely to be unemployed because of the pandemic (19.4% vs. 11.0%). Adjustment for interaction demonstrated a stronger negative association between social connectedness change and the psychosocial impact of COVID-19 for those with high-risk illness(es) (change in connectedness*chronic illness OR = 0.88, 95%CI: 0.79–0.98,p= 0.020). These findings inform our understanding of the distribution and intersection of responses to public health lockdown orders in the U.S. and build further evidence of the importance of social connectedness on psychological distress.