Microplastics (MPs) are ubiquitous in the environment and pose substantial threats to the water ecosystem. However, the impact of natural aging of MPs on their toxicity has rarely been considered. This study found that visible light irradiation with hydrogen peroxide at environmentally relevant concentration for 90 days significantly altered the physicochemical properties and mitigated the toxicity of polyamide (PA) fragments to infantile zebrafish. The size of PA particles was reduced from ∼8.13 to ∼6.37 μm, and nanoparticles were produced with a maximum yield of 5.03%. The end amino groups were volatilized, and abundant oxygen-containing groups (e.g., hydroxyl and carboxyl) and carbon-centered free radicals were generated, improving the hydrophilicity and colloidal stability of degraded MPs. Compared with pristine PA, the depuration of degraded MPs mediated by multixenobiotics resistance was much quicker, leading to markedly lower bioaccumulation in fish and weaker inhibition on musculoskeletal development. By integrating transcriptomics and transgenic zebrafish [Tg(lyz:EGFP)] tests, differences in macrophages-triggered proinflammatory effects, apoptosis via IL-17 signaling pathway, and antioxidant damages were identified as the underlying mechanisms for the attenuated toxicity of degraded MPs. This work highlights the importance of natural degradation on the toxicity of MPs, which has great implications for risk assessment of MPs.