In recent years, avocados have gained popularity as a nutritive food worldwide. This trend is causing a rise in the production of this edible fruit, which is accompanied by a number of problems associated with monocultural practices. Despite massive economic gains, limited molecular and structural information has been generated about avocado ripening. Consequently, we conducted a comparative proteomics study on avocado peel and pulp during the postharvest shelf life using tandem mass tag synchronous precursor selection triple-stage mass spectrometry (TMT-SPS-MS3). We were able to identify 3161 and 1128 proteins in the peel and pulp, respectively. The peels exhibited a major over-accumulation of proteins associated with water deprivation and oxidative stress, along with abscisic acid biosynthesis. Ethylene, jasmonic acid, phenylpropanoid, and flavonoid biosynthesis pathways were activated. Structurally, we observed the accumulation of lignin and the reduction of the cuticular thickness, which coincides with the reduction in the levels of long-chain acyl-coenzyme A (CoA) synthetase (LACS) and a marginal increase in 10,16-dihydroxyhexadecanoic acid.