The current study investigates the therapeutic and curative effect of Ulva lactuca polyphenolic extract (ULPE) in general and particularly polyphenolics compounds against heavy metal mixture (HME). The toxicity behind heavy metal is due to oxidative stress resulted from heavy metals pollution or administration through contaminated food (vegetables, water, and fish). Heavy metal toxicity plays a major role in different cardiovascular diseases. The objective of this study is aimed to examine the protective effect of ULPE against heavy metal mixture induced cardiovascular diseases through oxidative/antioxidant and inflammatory pathways. Sixty male rats (Sprague-Dawley) were assigned to six groups. Group I served as the control, group II served as the induced group receiving subcutaneously for 7 days 0.25 mg/100 gm body weight/day heavy metal mixtures (Equal concentration of Ni, Cd, Co and Hg chloride, and Pb acetate), group III received (i.p.) ULPE of dose 30 mg for 15 days, group IV served as the protected group pretreated with ULPE for 15 days as a protection dose, and then treated with the heavy metal-mixture, group V served as protected standard group pretreated with vitamin C (VitC ) (50 mg/Kg) and then treated with the heavy metal-mixture, and group VI served as standard group treated with VitC (50 mg/Kg). The main pathological changes within the heart revealed heart inflammation after heavy-metal mixtures administrations. On contrast to the protected group treated with ULPE (group IV), the protection group (group II) showed a significant increase in the antioxidant as well as anti-inflammatory biomarker. The cardiovascular biomarkers (Troponin T, CRP, and BNP) showed similar attitude elevations in induction group and decreased greatly in protection and VitC group. The antioxidant and the anti-inflammatory activities of ULPE are a consequence of their higher polyphenolic contents as well as marine secondary metabolites which are confirmed using qualitative and quantitative analysis. From the current result, we concluded that ULPE possesses a cardiovascular protective agent as a result of highly contents of different bioactive secondary metabolites which have antioxidant as well as free-radical scavenging and anti-inflammatory activates. Showed the mechanism of ULPE as cardioprotective against heavy metal mixture.