This study aimed to quantify the exposure-lag-response relationship between short-term changes in ambient temperature and absolute humidity and the transmission dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Japan. The prefecture-specific daily time-series of newly confirmed cases, meteorological variables, retail and recreation mobility, and Government Stringency Index were collected for all 47 prefectures of Japan for the study period from 15 February 2020 to 15 October 2022. Generalized conditional Gamma regression models were formulated with distributed lag nonlinear models by adopting the case-time-series design to assess the independent and interactive effects of ambient temperature and absolute humidity on the relative risk (RR) of the time-varying effective reproductive number (Rt). With reference to 17.8 °C, the corresponding cumulative RRs (95% confidence interval) at a mean ambient temperatures of 5.1 °C and 27.9 °C were 1.027 (1.016–1.038) and 0.982 (0.974–0.989), respectively, whereas those at an absolute humidity of 4.2 m/g3 and 20.6 m/g3 were 1.026 (1.017–1.036) and 0.995 (0.985–1.006), respectively, with reference to 10.6 m/g3. Both extremely hot and humid conditions synergistically and slightly reduced the Rt. Our findings provide a better understanding of how meteorological drivers shape the complex heterogeneous dynamics of SARS-CoV-2 in Japan.