The present study provides a systematic assessment of the relationships between climatic variables and major earthquakes (M > 6) in Iran (2011–2021). These variables include total cloud cover (tcc), low cloud cover (lcc), total precipitation (tp), surface latent heat flux (slhf), and total column rainwater (tcrw). Based on a wider set of variables provided by a multidimensional global dataset (ERA5), the combination of a cross-correlation function (CCF) and receiver operating characteristic (ROC) was used to develop the spatial and temporal analytic relations. Covering maximal values from 0.42 to 0.92, the CCF plots revealed that an increase in climatic parameters could provide valuable information about impending earthquake activity within 8 to 20 days. The mean values of tcc, lcc, tp, slhf, and tcrw were found to increase by 95%, 60%, 80.0 mm, 105 W/m2, and 95 kg−3/m2, respectively. In fact, with the mean AUC (area under the curve) indices ranging from 0.677 (tcc) to 0.810 (tcrw) prior to major earthquakes, the ROC plots allowed for discrimination between seismic and climatic variables ranging from “acceptable” to “excellent”. The changes in the climatic variables under study were due to anomalous air ionization and water condensation in the atmosphere, which can be regarded as short-term precursors to major earthquakes.