This review provides a comprehensive analysis of recent advancements in elucidating the molecular mechanisms underlying human immunodeficiency virus (HIV)-1 entry, focusing on the intricate interplay between the viral envelope glycoproteins (Env) and host cell receptors. We detail how structural insights into glycoprotein (gp)120-Cluster of Differentiation 4 (CD4)/coreceptor interactions and gp41-mediated membrane fusion inform therapeutic interventions, including fusion inhibitors and broadly neutralizing antibodies (bnAbs). The HIV-1 Env trimer undergoes a series of highly coordinated conformational transitions from a metastable prefusion state to a stable postfusion structure. CD4 engagement induces allosteric remodeling of gp120, unveiling coreceptor (C-C chemokine receptor type 5 (CCR5)/C-X-C chemokine receptor type 4 (CXCR4)) binding sites and priming gp41 activation. Fusion peptide insertion, six-helix bundle formation, and membrane merger are critical targets for inhibitors like T20 (enfuvirtide). Comparative analyses with other viruses reveal conserved fusion mechanisms despite distinct activation triggers, offering broader insights for antiviral development. By integrating structural biology, virology, and translational research, this review highlights how the mechanistic dissection of viral entry informs the design of next-generation therapeutics. We highlight strategies to disrupt Env-receptor interactions, block fusion intermediates, and harness cross-viral principles to counteract drug resistance and refine vaccine approaches. These insights not only deepen our understanding of HIV-1 pathogenesis but also drive the innovation of novel antiviral strategies.