This study examines the variability and change in the patterns of climatic extremes experienced in Indus-Delta of Sindh province of Pakistan, comprising regions of Karachi, Badin, Mohenjodaro, and Rohri. The homogenized daily minimum and maximum temperature and precipitation data for a 36-year period were used to calculate 13 and 11 indices of temperature and precipitation extremes with the help of RClimDex, a program written in the statistical software package R. A non-parametric Mann–Kendall test and Sen’s slope estimates were used to determine the statistical significance and magnitude of the calculated trend. Temperatures of summer days and tropical nights increased in the region with overall significant warming trends for monthly maximum temperature as well as for warm days and nights reflecting dry conditions in the study area. The warm extremes and nighttime temperature indices showed greater trends than cold extremes and daytime indices depicting an overall warming trends in the Delta. Historic decrease in the acreage of major crops and over 33% decrease in agriculture credit for Sindh are the indicators of adverse impacts of warmer and drier weather on Sindh agriculture. Trends reported for Karachi and Badin are expected to decrease rice cultivation, hatching of fisheries, and mangroves forest surrounding these cities. Increase in the prevailing temperature trends will lead to increasingly hotter and drier summers resulting to constraints on cotton, wheat, and rice yield in Rohri and Mohenjodaro areas due to increased crop water requirements that may be met with additional groundwater pumping; nonetheless, the depleted groundwater resources would have a direct impact on the region’s economy.