Hepatic and cardiovascular diseases (CVDs) remain major global health challenges; synthetic hepatoprotective agents used in clinical practices often lack therapeutic efficacy with undesirable side effects. Hepatic diseases are often associated with the progression of subclinical and clinical CVDs. It is evident from clinical data that coronary artery disease (CAD), arrhythmias, and stroke are more common in patients with hepatic impairments, which results in increased cardiovascular morbidity and mortality. The widespread availability, affordability, and evidence of efficacy in preclinical studies are the major reasons for the use of herbal medicines in previous times and their ever-increasing popularity in the current period. The available anecdotal information on the therapeutic benefits of herbal medicines cannot replace the rigor of clinical trials necessary to establish their safety and efficacy. This chapter aims to evaluate the efficacy of the herbal treatment as demonstrated in clinical trials. We have collected and tabulated the clinically evaluated hepatoprotective and CVD-protective herbals and their natural formulations with their current status in different trial stages. Literature was searched across three major databases PubMed, Web of Science, and Scopus to identify relevant clinical studies and ongoing current clinical trials evaluating the effectiveness and safety of herbal treatments. At present, berberine and silymarin have been approved by the US FDA to enter clinical phase IV studies. Compounds such as quercetin, resveratrol, allicin, and many others, offer promising cardiovascular protective effects. This chapter addresses the challenges of herbal treatments, particularly the poor bioavailability of active phytoconstituents, by utilizing nanoformulation-based strategies. To make herbal treatment more effective, the personalized, customized, and tailored herbal therapy approaches from a future development point of view have been discussed in detail.