In current years, the harm of pesticide residual pollution to environmental ecology and human health has obtained increasing attention. Hydroxylamine (HA) promoted activation of persulfate (PS) by the natural metallic sulfide mineral chalcopyrite (CuFeS2) for the removal of pesticide chlorpyrifos (CPF) and imidacloprid (IMP) in water had been systematically investigated in this study. Experimental results showed that HA could greatly accelerate the regeneration of Cu2+ and Fe3+ in solutions for PS decomposition. Nearly 99% of CPF removal by CuFeS2/PS/HA process was achieved within 80 min under optimal conditions. The decomposition of PS in the CuFeS2/PS/HA process was higher than that in the CuFeS2/PS process. Several coexisting cations (ie., Ca2+, Mg2+ and Al3+) and anions (ie., HCO3− and HPO42−) presented different levels of negative effects on CPF removal. Both HO• and SO4•− were generated in the CuFeS2/PS/HA process, and HO• might be the main reactive species responsible for the removal of CPF. The synchronized removal of CPF and IMP by CuFeS2/PS/HA process had been successfully achieved under certain conditions. The possible pathways of CPF degradation and enhanced mechanism for both CPF and IMP removal by CuFeS2/PS/HA process were thereby proposed. This study highlights the applications of CuFeS2/PS/HA process for the remediation of multiple pesticides-polluted wastewaters.