In a diversified cropping system, the tillage methods and weed management practices significantly influence the soil microbiome, which affects crop productivity. The synergetic impacts of such practices on the soil microbiome in association with yield under cotton–maize–Sesbania rostrata rotation with CA have not been extensively explored thus far in southern India. Therefore, a 4-year CA experiment was undertaken to investigate the impact of tillage and weed management on the soil microbiome and fungal diversity at 30 DAS and on the tasselling of maize and crop yield and to identify sustainable tillage and weed management practices that can provide nature-based solutions. The three tillage practices used were T1: CT(C)-CT(M)-fallow (NSr), T2: CT(C)-ZT(M)-ZT(Sr) and T3: ZT+R(C)-ZT+R(M)-ZT+R(Sr), and the following weed control tactics were used: W1-chemical weed control, W2-chemical (herbicide) rotation, W3- integrated weed management (IWM) and the W4-non-weeded control. Rhizosphere soil and rhizoplane samples were collected from the respective plots at 30 DAS after herbicide application and tasselling. Analysis of the microbial population and enzyme and microbial activities, viz., soil basal respiration (SBR), metabolic quotient (qCO2), microbial quotient (qMB), and soil microbial biomass carbon (SMBC) and nitrogen (SMBN), was performed following standard procedures. rRNA gene sequencing of 18S rRNA was performed with rhizosphere soil and rhizoplane fungi isolated at tasselling. The yield was recorded at harvest. The salient findings indicated a decrease in enzyme activity, microbial population, and microbial activity at the initial stage (30 DAS) due to the impact of herbicides, which subsequently increased in response to tasselling, except for qCO2, which decreased. These biological properties were greater in the T3 treatment and nonweeded control followed by IWM, except for qCO2, which showed a decreasing trend relative to T1 and T2 and W1 and W2 at both sampling stages of maize. K yield (KY) and system yield (SY) were greater in the T3, IWM, and herbicide-treated plots (W1 and W2) than in the T1, T2 and nonweeded control plots. Talaromyces flavus, a beneficial rhizosphere soil inhabitant, was identified in T3 in combination with the IWM. Considering both crop productivity and soil biological assessment, T3 and IWM were considered the best treatment combinations among all the other treatments with SY (4453 kg ha-1). These findings signify the importance of adopting reduced tillage (T3) and IWM for farmers while striving for nature-based solutions.