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In recent years, scarcity of water, energy and labour, increasing production cost, decreasing farm profitability and climate-change-induced variability are major challenges faced by the farmers in the Indo-Gangetic Plains (IGP) of South Asia. Conservation agriculture (CA) based best-bet crop management practices may increase crop productivity and profitability, while conserving natural resources. In a 10-year (2007-2017) field study, we assessed the effects of four combinations of tillage and, crop establishment (TCE), and residue (R) management options for the crop and water productivity and profitability of rice-maize (RM) system in Eastern IGP of India. The treatments consisted of zero-till direct seeded rice followed by zero tilled maize (ZTDSR/ZTM); ZTDSR followed by maize both on permanent raised beds with residue (PBDSR/PBM (+R)); PBDSR followed by PBM without residue (PBDSR/PBM (-R)) and conventional till puddled transplanted rice followed by conventional till maize (PTF/CTM). Overall, mean rice grain yield was similar under ZTDSR/ZTM, PBDSR/PBM (+R) and PTR/CTM, but 5.0-7.9% higher than PBDSR/PBM (-R). However, the maize yield was significantly (P < 0.05) higher by 6-82% in CA-based PBDSR/PBM (+R) RM system compared to PTR/CTM and PBDSR/PBM (-R) right from first year onwards. The RM system productivity (rice equivalent yield, REY) was higher by 1.5-38% in CA-based systems [ZTDSR/ZTM; PBDSR/PBM (+R)] than in the PTR/CTM and PBDSR/PBM (-R) systems. APSIM model predicted yield of rice and maize under different TCE and residue management practices with cumulative probability distribution plots was higher and consistent in PBDSR/PBM (+R) and ZTDSR/ZTM compared to PBDSR/PBM (-R) and PTR/CTM, suggesting that CA plots has lower probability of low yield than CT. CA-based ZTDSR/ZTM and PBDSR/PBM (+R) practices reduced the total system water use by 151-341 mm and 212-423 mm, and resulted enhanced system water productivity (WP) by 27-57% and 39-68%, respectively compared to CT (PTR/CTM) system. Economic profit for RM system was always significantly (P < 0.05) higher (225-1028 US$/ha/year) in CA-based systems than in CT system. Our study shows that CA-based system under RM rotation is one of the ways for improving crop and water productivity and farm income, as well as sustaining the natural resources in smallholder production systems of Eastern IGP in India and other similar agro-ecologies of South Asia.