The excessive use of chemical fertilizers has resulted in a decline in soil quality, crop yield, and crop quality. Partial substitution of chemical fertilizers with organic fertilizers is a sustainable practice that can alleviate these issues. However, a comprehensive evaluation of the effects of partial organic substitution on muskmelon yield, quality, soil fertility, and economic benefits remains unclear. We conducted a greenhouse experiment with muskmelon production in Shandong, China, involving five treatments: no fertilization (CK); total chemical fertilizer (CON); only replacing base fertilizer with organic fertilizer (OPT); 15% (OF15) and 30% (OF30) organic substitution of chemical fertilizers based on optimized fertilization. Our results indicated that the partial organic substitution treatments (OF15 and OF30) improved yield by 5.60-11.9% compared to CON. Furthermore, the Vitamin C, soluble protein, and sugar content in muskmelon were higher in the OF15 and OF30 treatments than in the CON. Compared to the CON, organic substitution treatments significantly increased soil organic matter, total N, total K, alkaline-hydrolyzable, available P, and available K. Additionally, the economic benefit analysis revealed that OF15 and OF30 increased net benefits by 5.60-14.9% respectively, compared to CON. Collectively, these findings suggest that partial substitution of mineral fertilizer with organic fertilizer improves muskmelon productivity, enhances soil nutrients, and increases economic benefits.