Climate change (CC) is now a global challenge due to uncertainties on the drivers and the multifaceted nature of its impacts. It impacts many sectors such as agriculture, water supply, and global economies through temperature and precipitation, affecting many livelihoods. Although there are global, regional, and national studies on CC, their application to determine local CC occurence mitigation and adaptation measures is not ideal. Therefore, this study aimed to determine climate change trends in Lake Kyoga Basin using standardized precipitation and anomaly indexes. Short-term (39 years, 1981–2020) and long-term (59 years, 1961–2020) monthly data from eight strategic meteorological stations were acquired from the Uganda National Meteorological Authority and supplemented with satellite and model reanalysis climate datasets. Change in precipitation was determined by SPI-6, while SAI determined change in temperature. The Mann–Kendall test was used to determine the trend significance. Whereas two (Serere and Lira) long-term data stations showed significant changes in precipitation, all the short-term data stations showed a significant increasing trend. Decadal relative rainfall anomaly increased from 85.6–105 in 1981–1990 to 92.0–120.9 in 2011–2020, while mean temperature anomaly increased from 0.2–0.6 °C to 1.0–1.6 °C in the same period. The frequency of severe wet weather events was more than for dry weather events in many stations, indicating an increase in precipitation. Maximum, mean, and minimum temperatures increased, with resultant warmer nights. The findings showed that the Lake Kyoga basin is experiencing climate change, with both temperature and rainfall increasing spatially and temporarily. Climate change affects agriculture, which is the main economic activity, and causes the destruction of infrastructure from floods, landslides, and mudslides. The results of this study are helpful in pointing out climate change-affected areas, and hence for designing mitigation and adaption strategies for local communities by policy and decision-makers from relevant stakeholders.