Background Coronavirus Disease’s (COVID-19) rampant rise has caused numerous challenges to the already strained health infrastructure of Nepal. The combination of underlying geographic and socioeconomic risk factors, and Nepal’s unique challenges with its rural majority population, the influx of migrant workers returning during the pandemic and catastrophic monsoon flooding has potentiated disease spread. This review describes the country’s health sector response, key strategies, challenges and strengths, and provides lessons learned for future response. Methods Open access information from the Nepali government was used to describe the COVID-19 response plan and implementation. The World Health Organization’s weekly situation reports, United Nations documents, and local news articles were also reviewed to find key evolution of COVID-19 and challenges faced in response. Findings Nepal’s COVID-19 response strategy was detailed in the government’s Health Sector Emergency Response Plan (HSER) in May 2020, and the strategy can be divided into four main areas: public health and social measures, hospital-based intervention, management and oversight, and budget allocation. Nepal has had COVID-19 cases in all 7 provinces and 77 districts, and due to a large rural population, the sudden influx of more than 1.3 million people from reverse migration and massive monsoon floods contributed to the rise in community spread of the virus. The second wave (Delta wave) found Nepal with the worst viral replication in the world and collapsed the health infrastructure. Conclusion Nepal’s COVID-19 response was strained by its unique challenges and key lessons were identified from this review that will be needed for future pandemic and disaster response. These include early planning, data centralization, transparent leadership, clear communication and coordination between three tiers of government, private-public partnerships, and utilization of its working population.