Introducing alternative cultivars with enhanced water use efficiencies can help alleviate pressure on groundwater for crop irrigations in Mississippi (MS) Delta. A two-year field study was conducted in 2019–2020 to compare the water use efficiencies (WUE) of recently released and pre-released soybean {Glycine max (L.) Merr.} cultivars in maturity group (MG) III (‘P37A78’, ‘LG03-4561-14’), IV (‘Dyna-gro 4516x’, ‘DS25-1, DT97-4290’), and V (‘S12-1362’, ‘S14-16306’) in the MS Delta. The experimental design was a split-plot with cultivar as the first factor and the second factor was water variant irrigation (IR) and no irrigation (RF, rainfed), replicated three times. The MG IV cultivar Dyna-gro 4516x recorded the highest grain yield and WUE: grain yields were 4.58 Mg ha−1 and 3.89 Mg ha−1 under IR and RF, respectively in 2019, and 4.74 Mg ha−1 and 4.35 Mg ha−1 in 2020. The WUE were 7.2 and 6.9 kg ha−1 mm−1, respectively, in 2019 under IR and RF, and 13.4 and 16.9 kg ha−1 mm−1 in 2020. The data reveals that ‘Dyna-gro 4516x’ (MG IV), ‘LG03-4561-14’ (MG III), and ‘P37A78’ (MG III) are best adapted to the early soybean production system (ESPS) in MS Delta region for sustainable production for conserving water resources.