In a diversified cropping system, the kinds of tillage methods and weed management choices adopted exert a significant influence on soil microbiome which has a bearing on crop productivity. The synergetic impacts of such practices on 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-years CA experiment was undertaken to investigate the impact of tillage and weed management on soil microbiome and fungal diversity at 30 DAS and tasselling of maize, crop yield and identify a sustainable tillage and weed management which can provide nature-based solution. Three tillage practices; 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 weed control tactics involved; W1-chemical weed control, W2-chemical (herbicide) rotation, W3- integrated weed management (IWM) and W4-non-weeded control laid out in split-plot design. Rhizosphere soil and rhizoplane samples were collected from the respective plots at 30 DAS after herbicides application and tasselling. Analysis for microbial population, enzyme and microbial activities viz., soil basal respiration (SBR), metabolic quotient (qCO2), microbial quotient (qMB), soil microbial biomass carbon (SMBC) and nitrogen (SMBN) was done duly following standard procedures. The rRNA gene sequencing with 18s was performed with rhizosphere soil and rhizoplane fungi isolated at tasselling. Yield was recorded at harvest. The salient findings indicated; a decline in enzyme activities, microbial population, microbial activities at initial stages (30 DAS) due to impact of herbicides which later on increased by tasseling except qCO2 which decreased. These biological properties were higher under T3 and non-weeded control followed by IWM except qCO2 which showed a decreasing trend relative to T1, T2 and W1, W2 at both sampling stages of maize. Kernel yield (KY) and System yield (SY) were enhanced by T3 and IWM, herbicides treated plots (W1 and W2) compared to T1, T2 and non-weeded control. Talaromyces flavus, beneficially rhizosphere soil inhabitant was identified in T3 in combination with IWM. Considering both crop productivity and soil biological assessment, T3 and IWM was considered as best treatment combination among all others with SY (4453 kg ha− 1). These findings signify the importance of adopting reduced tillage (T3) and IWM for the farmer while striving for Nature-based solution.