This chapter aims to comprehensively review the impact of hormonal contraceptives, particularly combined oral contraceptives (COCs), on liver function and associated health risks. It explores how synthetic and natural estrogens influence hepatic processes, including enzyme activity, lipid metabolism, coagulation, and immune modulation, which contribute to risks such as venous thromboembolism (VTE), cholestasis, and inflammation. Ethinyl estradiol (EE) and estradiol (E2) are known to significantly alter hepatic function, as increase in sex hormone–binding globulin (SHBG), in the synthesis of coagulation factors leading to increased VTE, but also lipid metabolism and cholestasis through several mechanisms. To circumvent and minimize these liver undesired actions, the transdermal route is now preferred to the oral route for E2 administration in the hormonal treatment of menopause, but this route is not suitable for contraception. By comparing the effects of classical and novel estrogenic compounds, this chapter aims to highlight new opportunities in hormonal contraception, potentially offering safer and more personalized options for women’s health. Estetrol (E4) is a natural estrogen produced for the liver of the fetus of great apes. E4 emerges as a promising alternative with a distinct mechanism of action: unlike EE and E2, E4 selectively activates nuclear ERα, but has not extra-nuclear actions, also named membrane initiated signaling pathway. In addition, minimal changes in hepatic coagulation factors and SHBG levels are observed in COC using E4 at the dose of 15 mg/day, in striking contrast to the large changes elicited by EE. Non-oral contraceptive methods, like transdermal or vaginal routes, can also mitigate liver E2-related side effects by bypassing first-pass metabolism. These differences in pharmacological profile underscore their potential to provide effective contraception with significantly reduced hepatic and thromboembolic risks, particularly for women predisposed to liver or vascular complications.