Aerobic co-composting represents an effective method for the treatment of antibiotic fermentation residues. This study optimized the co-composting of abamectin mycelial dregs (AMDs), excess sludge, and maize straw using an orthogonal experimental design. Composting was performed at a mass ratio of 4:1:1 (dry weight) under varying initial C/N ratios (20:1-30:1), moisture contents (50%-70%), and microbial inoculant dosages (5%-15%). Key parameters monitored included physicochemical properties, abamectin removal efficiency (RRA), and residual abamectin levels in the final product. The treatment with C/N = 30:1, moisture content = 60%, and inoculant dosage = 5% resulted in the longest thermophilic phase (6 days), highest temperature (59°C), highest germination index (90.05%), and highest RRA (89.67%), along with the lowest final moisture (24.95%) and residual abamectin (0.34 mg/g). Multivariate analysis of variance indicated that initial C/N, moisture, and inoculant dosage significantly influenced compost properties and abamectin degradation. Range analysis further identified the optimal conditions as C/N = 30:1, moisture = 70%, and inoculant = 5%. Microbial diversity analysis revealed key genera involved in the process, including Saccharomonospora, Bacillus, Kroppenstedtia, and Aspergillus. This study confirms the feasibility of aerobic co-composting for AMD treatment and offers new insights into its microbial mechanisms.