Plasticizers/phthalates play a facilitating role in the development of cancer and help the tumor to grow and metastasize. Camptothecin (CPT) and its derivatives are known to have anticancer properties of inhibiting cell growth, promoting cell apoptosis, and increasing autophagy. Therefore, in this study, we investigated whether the presence of di(2-ethylhexyl) phthalate (DEHP) could hinder apoptosis and autophagy caused by CPT in non-small cell lung cancer (NSCLC) cells. We found that DEHP interferes with CPT-induced apoptosis and autophagy and increases the prosurvival pathway by reducing the DNA damage marker γ-H2AX and activating the Akt and NF-κB pathways. Furthermore, we also confirmed that combining DEHP with 3-MA has additive effects in inhibiting autophagy and apoptosis in NSCLC cells. Taken together, our findings show that DEHP could affect CPT-induced anticancer treatment and provide evidence to show that DEHP induces chemoresistance in CPT-based chemotherapy.