Purpose To determine if losing work during the COVID-19 pandemic is associated with mental and physical health status. To determine if social interactions and financial resources moderate the relationship between work loss and health. Methods Participants were Australians aged 18 + years that were employed in paid work prior to the COVID-19 pandemic who responded to an online or telephone survey from 27(th) March to 12(th) June 2020 as part of a prospective longitudinal cohort study. Outcome measures include Kessler-6 score > 18 indicating high psychological distress, and Short Form 12 (SF-12) mental health or physical health component score < = 45 indicating poor mental or physical health. Results The cohort consisted of 2,603 respondents, including groups who had lost their job (N = 541), were not working but remained employed (N = 613), were working less (N = 660), and whose work was unaffected (N = 789). Three groups experiencing work loss had greater odds of high psychological distress (AOR = 2.22-3.66), poor mental (AOR = 1.78-2.27) and physical health (AOR = 2.10-2.12) than the unaffected work group. Poor mental health was more common than poor physical health. The odds of high psychological distress (AOR = 5.43-8.36), poor mental (AOR = 1.92-4.53) and physical health (AOR = 1.93-3.90) were increased in those reporting fewer social interactions or less financial resources. Conclusion Losing work during the COVID-19 pandemic is associated with mental and physical health problems, and this relationship is moderated by social interactions and financial resources. Responses that increase financial security and enhance social connections may alleviate the health impacts of work loss. Registration Australian New Zealand Clinical Trials Registry: ACTRN12620000857909.