AIDS, caused by HIV-1, is a devastating condition that severely compromises the human immune system, often resulting in fatal consequences. The primary therapeutic approach for AIDS involves a combination of multiple agents, known as "cocktail therapy," aimed at maximizing and sustainably suppressing viral replication within patients. The ongoing discovery of novel compounds and the establishment of innovative research strategies have become the mandatory path to provide increasingly effective treatment options for AIDS. Peptide-based fusion inhibitors, exemplified as enfuvirtide, are able to target the six-helix bundle fusion core in HIV-1 envelope protein and function during the early stage of viral invasion. However, the prolonged and intensive use of enfuvirtide in clinical settings has posed significant challenges, including the emergence of drug resistance. N-peptide fusion inhibitors, whose sequences are different from enfuvirtide, exhibit potential anti-HIV-1 activity and inhibition of drug-resistant strains through the advanced coiled-coil conformation and are expected to serve as novel peptide inhibitors in the iteration of enfuvirtide. This paper provides a comprehensive summary of N-peptide fusion inhibitor research and development (R&D) to date, with the aim of providing investigators with prospective ideas for exploring antivirals.