The COVID-19 pandemic is anticipated to continue to the year 2022 and could lead to several business failures if entrepreneurs do not respond adequately. Thus, the purpose of this study is to introduce a framework that captures the impacts and potential responses to the ongoing pandemic. To do that, we conducted telephone interviews with ten entrepreneurs who operate enterprises within Nigeria. Data collected for analysis were transcribed, chronologically arranged, coded, and thematically analyzed using NVivo. Our findings revealed that, during the pandemic, businesses experienced limited opening hours, a decline in their clients' patronage, lower turnover, and employee demotivation. In response, business owners should consider re-strategizing their business activities, maintaining connections with clients, and exploiting available support measures. Our findings have profound theoretical and practical implications. For entrepreneurs and policymakers, they offer insights into the form of challenges confronting businesses during a pandemic. It also provides response activities that entrepreneurs could adopt to mitigate the impact of an epidemic on their enterprises’ performance. For the field of entrepreneurship, it advances the need to integrate public health (health-related issues) into entrepreneurship study and consider its multiple levels of influence on the performance of businesses.