Spinosad is a potent macrocyclic lactone insecticide produced by Saccharopolyspora spinosa. However, its industrial application is significantly constrained by inherently low fermentation yields. Enhancing precursor supply (e.g., malonyl-CoA) is a key strategy for improving biosynthesis efficiency. A high-yielding parental strain was developed through ribosome engineering and NTG mutagenesis. Subsequently, three rounds of recursive genome shuffling under malonate stress yielded the superior strain ZJ-43. This strain achieved a shake-flask titer of 904.74 mg/L (5.59-fold relative to the wild-type strain). Integrated multi-omics analysis revealed that the high-yielding phenotype of ZJ-43 was associated with metabolic redistribution and attenuated TCA cycle activity, malonyl-CoA pool expansion, and an endogenous stringent response that autonomously programs the timing of secondary metabolism. These coordinated adaptations enhanced tolerance to intracellular malonyl-CoA accumulation, accelerated early growth, modified morphological differentiation, and ultimately enabled efficient spinosad overproduction. Based on these findings, we overexpressed key bottleneck genes and optimized the malonate-supplemented fermentation medium, thereby maximizing the expansion of the malonyl-CoA precursor pool in ZJ-43::fadA-accD3V235W. This engineered strain achieved a final spinosad titer of 1522.21 mg/L (9.39-fold), Overall, this work establishes and validates an integrated strategy combining composite mutagenesis, stress-based screening, multi-omics analysis, and targeted optimization, which may provide a useful framework for improving secondary metabolite production in actinomycetes.