Production of added products from industrial byproducts is a challenge for the current natural product industry and the extraction field more generally. Therefore, the aim of this study is to valorize the selected Mediterranean crops that can be applied as antioxidants, natural chelating agents, or even as biosolvents or biofuels after special treatment. In this study, the wastes of popular Mediterranean plants were extracted via homogenizer-assisted extraction (HAE) by applying response surface methodology (RSM) to examine the effects of process parameters on the total biophenolic contents (TBCs) of their residues. Box–Behnken design model equations calculated for each system were found significant (p < 0.0001) with an adequate value of determination coefficient (R2). Olive leaf had the highest TBC content (58.62 mg-GAE/g-DW with 0.1 g sample, 42.5% ethanol at 6522.2 rpm for 2 min), followed by mandarin peel (27.79 mg-GAE/g-DW with 0.1 g sample, 34.24% ethanol at 8772 rpm for 1.99 min), grapefruit peel (21.12 mg-GAE/g-DW with 0.1 g sample, 42.33% ethanol at 5000 rpm for 1.125 min) and lemon peel (16.89 mg-GAE/g-DW with 0.1 g sample, 33.62% ethanol at 5007 rpm for 1.282 min). The antioxidant activities of the extracts were measured by several in vitro studies. The most prominent biophenols of the wastes were quantified by high performance liquid chromatography (HPLC). Fourier-transform infrared-attenuated total reflectance (FTIR-ATR) and atomic force microscopy (AFM) techniques were also used for characterization.