252Cf is a powerful spontaneous fission neutron source, characterized by its compact size, high intensity, continuous neutron fission, and low heat emission. It is an important radioisotope, used as a neutron source for the reactor startup and prompt γ-neutron detection. Possible pathways for preparation of 252Cf include reactor irradiation, accelerators, or underground thermonuclear explosions, with high flux reactor irradiation being the most important and effective approach for large-scale production. This paper employs a detailed burnup analysis program coupled with Monte Carlo simulations to evaluate the 252Cf production process, analyzing differences in production yield and efficiency under various neutron flux levels and energy spectra for typical target nuclei. The conversion characteristics of different target nuclei are discussed, and optimized irradiation schemes for 252Cf production in high flux reactors are proposed. This study examines the primary depletion chain in the reactor-based production of 252Cf and analyzes main intermediate nuclides. The findings reveal that the neutron spectrum in the irradiation channel significantly influences 252Cf yield, with the (n, γ) reaction being the primary factor affecting production efficiency. Enhancing the (n, γ) reaction cross-section of bottleneck nuclides through energy spectrum optimization can significantly improve productivity. This research also lays the foundation for optimizing irradiation schemes, target structures, and target arrangements in high flux reactors for 252Cf production.