Using the physically-based model of runoff formation ECOMAG (ECOlogical Model for Applied Geophysics), the response of the Kolyma River’s water regime to ongoing and projected climate changes has been investigated. To operate the ECOMAG model, which calculates daily water discharges for control sections, information was gathered on the characteristics of the land surface and watershed relief, as well as archives of daily observations from meteorological stations within the basin. The calibration and validation of the model, performed for two sections on the Kolyma River and two sections on its tributaries – the Bolshoy Anyuy and Yasachnaya rivers – demonstrated strong agreement between the modelled and observed water discharges for the Kolyma River. Moreover, the analysis of observed water discharges and those calculated by the ECOMAG model reveals similar changes in the water regime that occurred from 1979 to 2020, such as an increase in annual and summer-autumn runoff, and a decrease in the duration of the winter low-flow period. To assess potential changes in the Kolyma River’s runoff in the 21st century, numerical experiments were conducted using the ECOMAG hydrological model and an ensemble of four global climate models. Calculations were performed for the periods 2020–2039, 2040–2059, 2060–2079, and 2080–2099 for four different Representative Concentration Pathway (RCP) scenarios. Anomalies in annual runoff, peak water discharges, flood volumes, winter low-flow periods, and summer-autumn periods were considered. Under all scenarios, the calculations indicate an increase in the annual and summer-autumn runoff of the Kolyma River.