Historical and future projected changes in climatic patterns over the largest irrigated basin in the world, the Indus River Basin (IRB), threaten agricultural production and food security in Pakistan, in particular for vulnerable farming communities. To build a more detailed understanding of the impacts of climate change on agriculture s in the IRB, the present study analyzes (1) observed trends in average temperature, precipitation and related extreme indicators, as well as seasonal shifts over a recent historical period (1997–2016); and (2) statistically downscaled future projections (up to 2100) from a set of climate models in conjunction with crop-specific information for the four main crops of the IRB: wheat, cotton, rice and sugarcane. Key findings show an increasing trend of about over 0.1 °C/year in observed minimum temperature across the study area over the historical period, but no significant trend in maximum temperature. Historical precipitation shows a positive annual increase driven mainly by changes in August and September. Future projections highlight continued warming resulting in critical heat thresholds for the four crops analyzed being increasingly exceeded into the future, in particular in the Kharif season. Concurrently, inter-annual rainfall variability is projected to increase up to 10–20% by the end of the 21st century, augmenting uncertainty of water availability in the basin. These findings provide insight into the nature of recent climatic shifts in the IRB and emphasize the importance of using climate impact assessments to develop targeted investments and efficient adaptation measures to ensure resilience of agriculture in Pakistan into the future.