Catchments characteristics, such as geomorphology, geology, soil, land use, and climatic variables, play an important role in total stream flow responses, a critical resource for people and the environment. Most of the previous literatures were applied a conventional statistical regression model to assess the relationship between landscape-climate descriptors, and streamflow and PET. However, a conventional statistical regression model didn’t consider dependence of explanatory variables that were collected or extracted across both space and time. This paper investigated the impacts of landscape attributes and climate variables on catchment scale temporal variation of total streamflow and spatio-temporal variation of potential evapotranspiration (PET) in the Mille catchment using multiple linear regression techniques, and the importance of this study was to test spatial autocorrelation in the spatial regression model which is required to properly assess and quantify the relationship between hydrological regime response components and Landscape-climate descriptors in a catchment with topographically complex, and high spatio-temporal climatic variation like in our case study area, the Mille catchment. Statistical regression analysis revealed significant relationships between streamflow and climate variables, especially with rainfall. Mean maximum temperature is the most dominant factor controlling temporal variation of potential evapotranspiration at a monthly scale, whereas NDVI is the most significant factor that controls the spatial variability of PET. The multiple regression model shows that 91.1% of temporal variation in streamflow was accounted for rainfall, whereas, 96.6% and 78.4% of temporal and spatial variation in potential evapotranspiration was accounted for in maximum temperature and NDVI, respectively. Methods also can be applied to catchments with similar landscape attributes and climate variables.