Betulinic acid-derived human immunodeficiency virus type 1 (HIV-1) maturation inhibitors connect natural-product medicinal chemistry with inhibition of capsid–spacer peptide 1 (CA–SP1) processing. This critical narrative review examines how chemical modifications relate to target structure, conformational dynamics, antiviral activity and development limitations. C-3 pharmacophore replacement and modification of the C-28/C-17 region improved antiviral breadth and exposure, but improved cellular potency alone did not establish clinical differentiation. Cryo-electron microscopy, microcrystal electron diffraction and nuclear magnetic resonance support engagement of the CA–SP1 six-helix bundle and restriction of its dynamics. Molecular simulations offer an ensemble-based explanation whose interpretation depends on assembly state, cofactors, sampling and experimental validation. Binding kinetics and cleavage measurements provide particularly informative connections between molecular observations and antiviral activity. Later-generation compounds demonstrate that broader susceptibility coverage and favorable pharmacokinetics must be evaluated alongside tolerability, resistance and regimen requirements. Progress therefore depends on aligning compound identity, relevant target assemblies, experimentally constrained dynamics, and functional processing and exposure, while retaining negative and discordant findings.