In response to the problems of non-renewable and difficult degradation of current lubricants, a cottonseed oil (CSO) is modified into a highly nonyl-branched isodecyl esters (NIEs) bio-based lubricant in the work. The lubricant synthesized process undergoes hydrolysis-esterification-epoxidation-ring opening and branching steps, just in the presence of green, non-polluting lipases, and insoluble ionic liquid catalysts. The pour point (−47 °C) of NIEs is much lower than that of CSO (−3 °C), the kinematic viscosity at 40 °C (200.3 mm2/s) is much higher than CSO (32.55 mm2/s), and the viscosity index reaches 141, which exhibits excellent low-temperature fluidity and viscous-temperature performance. Moreover, its oxidation onset temperature is 307.21 °C and its oxidative induction time is 21 min, which far exceeds CSO (300.1 °C, 13 min), indicating its excellent thermal oxidation stability. In addition, in the high-frequency reciprocation test, the coefficient of friction (COF) is 0.07, the average wear scar diameter (AWSD) is 132 µm, and the oil film coverage rate (OFCR) is 100%, which is much superior to CSO (COF: 0.09, AWSD: 219 µm, OFCR: 92%) and commercially SN lubricants (COF: 0.11, AWSD: 196 µm, OFCR: 98%), indicating it is superior in reducing friction as a lubricant. In conclusion, the bio-based lubricant has the potential to replace mineral lubricants and the synthesis method provides a reference for the synthesis of such lubricants.