Abstract: Enping 21−4 in the Eastern South China Sea is a typical marginal oilfield. Certain risks and challenges are faced while drilling of ultra-deep extended reach wells in this oilfield, such as difficult hole cleaning, low pressure bearing capacity of unconsolidated sandstone, multiple faults encountered while drilling, large drag and torque, and restrictions during casing running, etc. In order to solve the drilling problems in this oilfield, BIODRILLS synthetic base drilling fluid was selected and optimized. The optimal synthetic base fluid, filtrate reducer, flow pattern regulator, and lubricant were determined, and the emulsifier dosage was optimized. The formula of BIODRILLS synthetic base drilling fluid was adjusted. The laboratory performance evaluation results show that the formula can maintain good and stable rheological properties, higher low shear rate, strong inhibition, plugging property, anti-pollution property, and excellent lubrication performance, with high temperature and high pressure filtration loss of 2.4 mL and extreme pressure lubrication coefficient of 0.03–0.06, and meet the requirements of ultra-deep long extended reach well drilling in Enping 21−4 Oilfield. The BIODRILLS synthetic base drilling fluid prepared according to the formula has been applied in the ultra-deep extended reach wells A1H and EP−X in the eastern South China Sea. The application shows that the system has stable performance, good cutting carrying capacity, and excellent lubrication performance. The drag coefficient during drilling ϕ 311.1 mm hole is 0.17–0.21, and the open hole drag coefficient is 0.40–0.45 when running ϕ244.5 mm casing. The drilling fluid has not only effectively solved the drilling problem of ultra-deep extended reach wells in the eastern South China Sea but also provided technical means for the drilling of 10 000-meter long extended reach wells in this sea area.