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Trehalose, spermidine, nicotinamide, and polyphenols have been shown to display pro-autophagic and antioxidant properties, eventually reducing cardiovascular and ischemic complications. This study aimed to investigate whether a mixture of these components improves maximal walking distance (MWD) in peripheral artery disease (PAD) patients. Nitrite/nitrate (NOx), endothelin-1, sNOX2-dp, H₂O₂ production, H₂O₂ break-down activity (HBA), ATG5 and P62 levels, flow-mediated dilation (FMD), and MWD were evaluated in 20 PAD patients randomly allocated to 10.5 g of mixture or no-treatment in a single-blind study. The above variables were assessed at baseline and 60 days after mixture ingestion. Compared with baseline, mixture intake significantly increased MWD (+91%; <i>p</i> < 0.01) and serum NOx (+96%; <i>p</i> < 0.001), whereas it significantly reduced endothelin-1 levels (−30%, <i>p</i> < 0.01). Moreover, mixture intake led to a remarkable reduction in sNOX2dp (−31%, <i>p</i> < 0.05) and H₂O₂ (−40%, <i>p</i> < 0.001) and potentiated antioxidant power (+110%, <i>p</i> < 0.001). Finally, mixture ingestion restored autophagy by increasing ATG5 (+43%, <i>p</i> < 0.01) and decreasing P62 (−29%, <i>p</i> < 0.05). No changes in the above-mentioned variables were observed in the no-treatment group. The treatment with a mixture of trehalose, spermidine, nicotinamide, and polyphenols improves MWD in PAD patients, with a mechanism possibly related to NOX2-mediated oxidative stress downregulation and autophagic flux upregulation. Clinical Trial Registration unique identifier: NCT04061070.