Global warming has accelerated climate and weather changes, impacting the regional water cycle. This study assesses the temporal trends of seasonal and annual runoff in the Chitral River Basin (CRB) and its responses to regional climatic factors (i.e., temperature, precipitation, and Normalized Difference Vegetation Index (NDVI)) and oceanic indices at large scales (i.e., El Nino Southern Oscillation (ENSO), Indian Ocean Dipole (IOD), and Pacific Decadal Oscillation (PDO)). The non-parametric Mann–Kendall (MK) test, the Sequential Mann–Kendall test (SQMK) and Sen Slope (SS) is used to evaluate trends and magnitude. In contrast, wavelet analysis is used to assess the coherence. In general, precipitation increases in winter, summer and autumn, whereas it decreases in spring. The temperature increased significantly in winter and spring, while a significant increase in seasonal and annual runoff was evident. Annual NDVI increased, whereas the Normalized Difference Water Index (NDWI) and the Normalized Difference Snow Index (NDSI) decreased. Generally, runoff has significant inter-annual coherences with regional environmental factors, and a significant coherence with NDVI. Monthly runoff has a positive coherence with temperature and NDVI, whereas it has a negative correlation with precipitation, NDWI, and NDSI. In general, ENSO, IOD and PDO show a positive correlation with runoff. The MWC findings indicate that annual runoff prevailed interannual signals with local environmental factors and with the Pacific Ocean, whereas interannual and interdecadal coherences are obvious with the Atlantic Ocean. The results have significant implications for decision-makers seeking to enhance water resource planning, disaster prevention, and mitigation, especially in global warming and the intensification of human activities that influence hydroclimatic changes at high altitudes.