In the present study we mined the information on Gardenia lucida (Dikamali) and identified seven polymethoxyflavones from its gum resin. We also investigated its antiproliferative and antioxidant potential. Xanthomicrol (8) found as potent DPPH scavenger (85.86±1.3%) along with strong ferric plummeting ability (53.60±2.0 FSE) and reducing potential (1.07±0.01) as compared to ascorbic acid. Gardenin B (5) strongly inhibit biochemical production of nitric oxide (IC₅₀ 10.59±0.4μg/mL) followed by 5-Desmethylnobiletin (7) and Gardenin E (10, IC₅₀11.01±0.7–34.53±2.7μg/mL). Methanol extract, chloroform fraction and Acerosin (11), Gardenin D (9) and Gardenin B (5) exhibited superior antiproliferative activity against lung, breast, colon, hepatic and leukaemia cell lines as well as in keratinocytes (IC₅₀ 12.82±0.67–94.63±1.27μg/mL) whereas other fractions and isolated compounds moderately affect the cell proliferation (21.40±0.12–48.12±0.47%) with least and non-specific interaction against succinate dehydrogenase. Except compound 2, 3, 6, 8 and 11, others were found as a significant inhibitor of ODC (IC₅₀ 2.36±0.7–8.53±0.32μg/mL) with respect to DFMO (IC₅₀ 10.85±0.28μg/mL). In silico analysis also revealed enervated binding energy (−4.30 to −5.02kcal/mol) and inhibition constant (704.18–210.26μM) wherein 5, 7, 8, 9 and 10 showed specific interaction with the receptor while rest were non-specific. Except butanol fraction and Gardenin E, others were potently inhibited the cathepsin D activity with non-specific interaction and better binding energy (−5.78 to −7.24kcal/mol) and inhibition constant (57.87–4.90μM). In conclusion, it can be interpreted that isolated polymethoxyflavones (Gardenin B, 5-Desmethylnobiletin, Gardenin E) could be taken up as a lead for target specific studies. Methanol extract and chloroform fraction prevails in all the tested activity therefore cumulative and composite intervention of polymethoxyflavones present in it reveals its pharmacological attributes and traditional value.