A molecular-level approach is developed to prevent or inhibit the degradation processes of alkanethiol self-assembled monolayers (SAMs). Previous studies revealed two degradation pathways: direct desorption and oxidation-desorption. By use of scanning tunneling microscopy (STM) and atomic force microscopy (AFM), in situ and time-dependent imaging reveals and confirms that degradations of alkanethiol SAMs on gold mainly initiate at defect sites, such as domain boundaries and vacancy islands, and then propagate into the ordered domains. Our approach targets at attaching small molecules with preferred adhesion to the defects. The best candidates are aqueous media containing a small amount of amphiphilic surfactant molecules, such as NN-dimethylformamide (DMF) or dimethyl sulfoxide (DMSO). High-resolution studies demonstrate that DMSO and DMF molecules attach to SAM surfaces and more favorably at defect sites, forming relatively stable adsorbates. This attachment increases the activation energy sufficiently to inhibit both degradation pathways. The robustness of this approach has been investigated as a function of surfactant concentration, solution temperature, and the stirring condition. Molecular-level mechanisms and energetics for degradation inhibition of SAMs are also discussed in detail.