The vast majority of patients with hepatocellular carcinoma (HCC) in China originate from hepatitis B cirrhosis, while 90% of cirrhotic patients may develop portal hypertension, and the HCC patients with portal hypertension account for 15%-30%. Portal hypertension is a group of clinical syndromes characterized by elevated portal venous pressure and formation of portal-systemic collateral circulation, and it is one of the most important complications of liver cirrhosis. HCC and portal hypertension affect each other, and portal hypertension seriously affects the prognosis of HCC patients. The development of systemic treatment regimens for HCC provides more treatment options for patients with advanced HCC, including molecular-targeted drug therapy, immunotherapy, and chemotherapy. Different systemic therapeutic drugs for HCC have different impacts on portal hypertension, and this article reviews the effect of commonly used systemic therapeutic drugs for HCC on portal hypertension.