The present study focuses on the cosmeceutical and medicinal importance of Dalbergia sissoo Roxb. extracts. Aqueous extracts of leaves, fruits and bark were screened for the antioxidant, UV protection potential, DNA protective and cytotoxic activity. Among the tested extracts, bark aqueous extract (BAE) was the most bioactive extract in respect to free radical scavenging (FRS) activity having antioxidant activity index (AAI) of 2.73 by DPPH method, IC50 value of 10.02 ± 0.479 μg/mL by ABTS scavenging assay and FRAP value of 134.98 ± 0.007 mg TE/g dry extract. In addition, sun protection factor (SPF 39.38 ± 0.07) and anti-proliferative activity against B16 mouse melanoma (IC50 0.221 mg/mL) were also highest in BAE with comparatively low selectivity index (SI) 1.89 ± 0.26. Leaves aqueous extract (LAE) had highest SI (8.69 ± 2.41) but lower cytotoxicity (0.302 ± 0.033 mg/mL) towards B16. Fruits aqueous extract (FAE) showed plasmid DNA protection against H2O2 stress in a dose dependent manner. The ct DNA-BAE interaction study reveals non-covalent interaction with a slight shift of λmax from 210 nm (BAE alone) to 220 nm (BAE-ct DNA complex). High antioxidant, SPF and KUVB (3.93 ± 0.005) and KUVA (3.95 ± 0.005) values of BAE project its incorporation in sunscreen formulations as photoprotective principle. Anti-proliferative activity and DNA interacting potential indicates these extracts can be evaluated further for management and prevention of skin cancers.