Neutrophil extracellular traps (NETs) are complex structures released by activated neutrophils during inflammatory responses. Due to their unique potential for causing tissue damage and modulating immune responses, there is increasing interest in studying these structures as potential targets for the treatment of infectious diseases, autoimmune diseases, and cancer. However, therapeutic targeting of NETs might trigger deleterious effects that may limit treatment efficacy. NET disruption may increase the microbial load in infection; in autoimmunity, NET targeting might impair peripheral tolerance, but it might reduce adaptive immune responses in cancer. In this review, we explore the therapeutic and deleterious effects of NET-targeted therapy while shedding light on novel strategies to overcome treatment-related limitations and enhance treatment efficacy.