Characterizing the physiological mechanisms behind major-effect drought-yield quantitative trait loci (QTLs) can provide an understanding of the function of the QTLs—as well as plant responses to drought in general. In this study, we characterized rice (Oryza sativa L.) genotypes with QTLs derived from drought-tolerant traditional variety AdaySel that were introgressed into drought-susceptible high-yielding variety IR64, one of the most popular megavarieties in South Asian rainfed lowland systems. Of the different combinations of the four QTLs evaluated, genotypes with two QTLs (qDTY2.2 + qDTY4.1 ) showed the greatest degree of improvement under drought compared with IR64 in terms of yield, canopy temperature, and normalized difference vegetation index (NDVI). Furthermore, qDTY2.2 and qDTY4.1 showed a potential for complementarity in that they were each most effective under different severities of drought stress. Multiple drought-response mechanisms were observed to be conferred in the genotypes with the two-QTL combination: higher root hydraulic conductivity and in some cases greater root growth at depth. As evidenced by multiple leaf water status and plant growth indicators, these traits affected transpiration but not transpiration efficiency or harvest index. The results from this study highlight the complex interactions among major-effect drought-yield QTLs and the drought-response traits they confer, and the need to evaluate the optimal combinations of QTLs that complement each other when present in a common genetic background.