The exploration of citrus waste valorization extends beyond its environmental benefits to encompass potential health implications, particularly in cancer prevention. The bioactive compounds extracted from citrus waste, notably polyphenols like quercetin, gallic acid, hesperidin, and ferulic acid, hold promising anti-cancer properties. Research suggests that these compounds exhibit potent antioxidant and anti-inflammatory effects, which are integral in combating carcinogenesis. Quercetin, a flavonoid abundantly found in citrus extracts, has garnered attention for its ability to inhibit cancer cell proliferation and induce apoptosis, thereby impeding tumor growth. Gallic acid, another prevalent compound, demonstrates anticancer potential through its modulation of signaling pathways associated with cell survival and proliferation. Hesperidin, known for its antioxidative properties, has shown promise in suppressing tumor growth and metastasis by targeting various molecular pathways involved in cancer progression. Ferulic acid, renowned for its anti-inflammatory and antioxidant activities, exhibits chemopreventive effects by inhibiting carcinogen activation and promoting detoxification processes within the body. The present study compares conventional (soxhlet, maceration) and non-conventional (ultrasound, microwave) techniques to obtain these polyphenols from mandarin peels. The maximum total phenolic content of 3.78 mg GAE/ g dry peels and DPPH activity of 69.89% was observed using 80% methanol and ultrasound assisted extraction. The presence of these compounds was confirmed using advanced analytical methods such as FT-IR and HPLC. The phenolic compounds (mg/g dry peels) such as gallic acid (0.29 ± 1.08), p-coumaric acid (0.17 ± 0.52), chlorogenic acid (0.30 ± 0.56), ferulic acid (1.49 ± 1.36), hesperidin (1.34 ± 0.51), naringenin (0.56 ± 0.94), and quercetin (0.33 ± 1.02), observed during UAE were 25–35% higher values compared to other techniques. By harnessing the bioactive potential of citrus waste-derived compounds, particularly for cancer prevention, this study contributes to both environmental sustainability and human health enhancement, paving the way for innovative strategies in functional food development and nutraceutical applications.