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Intensive mono-cropping without a balanced supply of nutrients and declining water resources are degrading soil health, and as a consequence, agriculture production is becoming unsustainable and causing environmental degradation. The field experiment was conducted during Rabi season to assess the effect of an irrigation schedule, nutrient management, and wheat (Triticum aestivum L.) varieties on soil microbial biomass carbon (SMBC) and soil enzymes activities. Two nutrient levels, recommended rate of chemical fertilizer (RDF) and 50% RDF + 50% recommended dose of nitrogen (RDN) through farmyard manure (FYM) designated as Integrated Nutrient Sources (INS), and three irrigations levels, one irrigation at crown root initiation (CRI), two irrigations at CRI and flowering stages, and five irrigations at all main stages of the crop (CRI, tillering, jointing, flowering, and grain filling) were allocated to main-plots while four varieties of wheat, HD 2967, WR 544, HD 2987, and HD 2932, were allocated to sub-plots. The results revealed that SMBC and activities of dehydrogenase, alkaline phosphatase enzymes, and acid phosphatase were higher under restricted irrigation (irrigation at CRI stage) than other irrigation schedules. SMBC, dehydrogenase, acid phosphatase, and alkaline phosphatase activities were 73.0 µg g soil−1, 86.0 µg TPF g soil−1d−1, 39.6 µg PNP g soil−1 h1, and 81.8 µg PNP g−1 soil h−1, respectively, with the use of INS that was higher than RDF. Root weight and root volume followed a similar pattern. Applying single irrigation at CRI left behind the maximum available nitrogen (166.4 kg ha−1) in soil compared to other irrigation schedules and it was highest (149.31 kg ha−1) with the use of INS. Moreover, total organic carbon (TOC) was 0.44 and 0.43% higher with irrigation at CRI stages and the use of INS, respectively. The INS with single irrigation at the CRI stage is important to improve the root growth, SMBC dehydrogenase, alkaline phosphatase, and acid phosphatase enzyme activity in the wheat production system. [ABSTRACT FROM AUTHOR]