Enhancement of rice (Oryza sativa L.) productivity under rainfed ecosystems is important to food security. Efforts to increase yield have had little success, mainly due to the complexity of inheritance of abiotic stress tolerance traits and the technical challenges of phenotyping these traits. The study was conducted to pyramid quantitative trait loci (QTLs) governing tolerance to moisture and heat stress from cv. Nagina22 and QTLs for high yield traits from variety IR64, with the aid of marker-assisted pedigree breeding. From the IR64/N22 cross, we identified 14 pyramided lines with various combinations of targeted QTLs (5–11 QTLs). The three best lines that performed well under moisture stress conditions were PL76 with two water-use efficiency (WUE) QTLs (Mr19a, SLA 9.1), three drought-tolerant yield (DTY) QTLs (qDTY1.2, qDTY3.2, qDTY6.1), one heat-tolerance (HT) QTL (qSSPF10) and four yield QTLs (qFLW4.1, qFLL9, LP1, GW5); PL476 with two WUE QTLs (%N11.1, qWue7a), two DTY QTLs (qDTY6.1, qDTY12.1), two HT QTLs (qSSP_F10, qHT6) and three yield QTLs (qFLW4.1, qFLL9, LP1); and PL130 with two WUE QTLs (Mr19a, qWue7a), four DTY QTLs (qDTY1.2, qDTY3.2, qDTY4.1, qDTY12.1), two HT QTLs (qSSPF10, qHT6) and two yield QTLs (qFLW4.1, LP1). These three lines shown a yield advantage of 51.93%, 55.93% and 60.30%, respectively, over high-yielding IR64. Under heat stress, PL457 and PL130 with HT QTLs qSSP_F10 and qHT6 showed 85.02% and 61.55% yield advantage, respectively, over IR64. In conclusion, we have demonstrated that the systematic combination of important QTLs from two contrasting parents through marker-assisted pedigree breeding is an outstanding approach to supplement conventional phenotype-based pedigree breeding, especially to improve complex traits such as yield and tolerance to moisture stress and heat.