Consumer interest in health-promoting foods has prompted researchers to use wine by-products to increase food’s functional characteristics. This research aims to examine the skin bioactivities of Samos white (small-berry Muscat) and red (Augustiatis) grape skin extracts (M-GSkE, A-GSkE). Total phenolic content, antiradical activity, the inhibition of plasma oxidation and platelet aggregation, and the phenolic profile were examined. A-GSkE and M-GSkE showed high total phenolics (1.19 ± 0.13 vs. 2.12 ± 0.23 mM GAE), antiradical activity (7.7 ± 0.4 vs. 6.6 ± 0.3 μM GAE for ABTS; 31.12 ± 0.8 vs. 26.4 ± 1.0 μM GAE for DPPH), resistance to plasma oxidation (5.7 ± 0.4 vs. 1.1 ± 0.2 μM GAE), and antithrombotic activity (19.7 ± 0.1 vs. 26.6 ± 0.2 μM GAE). Ferulic (41.3 ± 0.1 > 13.2 ± 0.1 μg/g DM), vanillic (26.3 ± 1.7 > 12.2 ± 1.2 μg/g DM), and gallic (16.6 ± 0.1 > 8.4 ± 2.9 μg/g DM) acids along with ε-viniferin (3.6 ± 0.4 > 2.8 ± 0.3 μg/g DM) were identified in higher content in A-GSkE. Catechin (59.8 ± 1.5 μg/g DM), chlorogenic acid (43.8 ± 0.9 μg/g DM), and resveratrol (0.83 ± 0.13 μg/g DM) were identified only in M-GSkE, while caffeic acid 19.8 ± 0.4 μg/g DM) and daidzein (16.8 ± 0.1 μg/g DM) were identified only in A-GSkE. The specialized bioactivities researched in two previously unexplored Samos’ wine grape skin extracts give them added value. The valorization of such by-products promises a sustainable future in the food sector of local communities and an improvement in local public health.