Grape pomace is a potential source of natural antioxidant agents. Phenolic compounds and antioxidant and cardioprotective properties of fresh and fermented pomace extracts obtained from Vitis vinifera L. red variety Fetească neagră grown in Romania in 2015 were investigated. Grape pomace extracts total phenolic index, total tannins, total anthocyanins, proanthocyanidins, flavan-3-ol monomers, stilbenes, and DPPH free radical scavenger were measured. The effect of a seven-day pretreatment with grape pomace extracts on the isoprenaline-induced infarct-like lesion in rats was assessed by ECG monitoring, serum levels of creatine kinase, aspartate transaminase, and alanine transaminase. Total serum oxidative status, total antioxidant response, oxidative stress index, malondialdehyde, total thiols, and nitric oxide have been also assessed. Higher phenolic content and antioxidant activity were found in fermented pomace extracts when compared to fresh pomace extracts. Pretreatment with grape pomace extracts significantly improved cardiac and oxidative stress parameters. In conclusion, Fetească neagră pomace extracts had a good in vitro antioxidant activity due to an important phenolic content. In vivo, the extracts had cardioprotective effects against isoprenaline-induced infarct-like lesion by reducing oxidative stress, fresh pomace extracts having a better effect.