Unique, variable summer climate of the lower Mississippi (MS) Delta region poses a critical challenge to cotton producers in deciding when to plant for optimized production. Traditional 2-4 year agronomic field trials conducted in this area fail to capture the effects of long-term climate variabilities in the location for developing reliable planting windows for producers. Our objective was to integrate a four-year planting-date field experiment conducted at Stoneville, MS during 2005-2008 with long-term climate data in an agricultural system model and develop optimum planting windows for cotton under both irrigated and rainfed conditions. Weather data collected at this location from 1960 to 2015 and the CSM-CROPGRO-Cotton v4.6 model within the Root Zone Water Quality Model (RZWQM2) were used. The cotton model was able to simulate both the variable planting date and variable water regimes reasonably well: relative errors of seed cotton yield, aboveground biomass, and leaf area index (LAI) were 14%, 12%, and 21% under rainfed conditions and 8%, 16%, and 15% under irrigated conditions, respectively. Planting windows under both rainfed and irrigated conditions extended from mid-March to mid-June: windows from mid-March to the last week of May under rainfed conditions, and from the last week of April to the end of May under irrigated conditions were better suited for optimum yield returns. Within these windows, rainfed cotton tends to lose yield from later plantings, but irrigated cotton benefits; however, irrigation requirements increase as the planting windows advance in time. Irrigated cotton produced about 1000 kg·ha −1 seed cotton more than rainfed cotton, with irrigation water requirements averaging 15 cm per season. Under rainfed conditions, there is a 5%, 14%, and 27% chance that the seed cotton production is below 1000, 1500, and 2000 kg·ha −1 , respectively. Information developed in this paper can help MS farmers in decision support for cotton planting.