Although vaccines have become available, emergence and rapid transmission of new variants have added new paradigm in the coronavirus disease-2019 (COVID-19) pandemic. Weather, population and host immunity have been detected as the regulatory elements of COVID-19. This study aims to investigate the effects of weather, population and host factors on the outcome of COVID-19 and mutation frequency in Japan. Data were collected during January 2020 to February 2021. About 92% isolates were form GR clades. Variants 501Y.V1 (53%) and 452R.V1 (24%) were most prevalent in Japan. The strongest correlation was detected between fatalities and population density (rs = 0.81) followed by total population (rs = 0.72). Relative humidity had the highest correlation (rs = −0.71) with the case fatality rate. Cluster mutations namely N501Y (45%), E484K (30%), N439K (16%), K417N (6%) and T478I (3%) at spike protein have increased during January to February 2021. Above 90% fatality was detected in patients aged >60 years. The ratio of male to female patients of COVID-19 was 1.35:1. This study will help to understand the seasonality of COVID-19 and impact of weather on the outcome which will add knowledge to reduce the health burden of COVID-19 by the international organisations and policy makers.