We conducted 131 semi-structured phone interviews with householders in rural Odisha, India to explore participants’ COVID-19 related knowledge, perceptions, and preventative actions, as well as how the pandemic affected their daily life, economic and food security, and the village-level response. Interviews were conducted with 73 heads of household, 37 primary caregivers, and 21 members of village water and sanitation committees from 43 rural villages in Ganjam and Gajapati districts in Odisha state. The study took place between May–July 2020 throughout various lockdown restrictions and at a time when many migrant workers were returning to their villages and cases were rising. Most respondents could name at least one correct symptom of COVID-19 (75%), but there was lower knowledge about causes of the disease and high-risk groups, and overall COVID-19 knowledge was lowest among caregivers. Respondents reported high compliance with important preventative measures, including staying home as much as possible (94%), social distancing (91%), washing hands frequently (96%), and wearing a facial mask (95%). Additionally, many respondents reported job loss (31%), financial challenges (93%), challenges related to staying home whether as a preventative measure or due to lockdowns (57%), changes in types and/or amount of food consumed (61%), and adverse emotional effects as a result of the pandemic and lockdown. We also provide detailed summaries of qualitative responses to allow for deeper insights into the lived experience of villagers during this pandemic. Although the research revealed high compliance with preventative measures, the pandemic and associated lockdowns also led to many challenges and hardships faced in daily life particularly around job loss, economic security, food security, and emotional wellbeing. The results underscore the vulnerability of marginalized populations to the pandemic and the need for measures that increase resilience to large-scale shocks.