Since the surface of human skull is irregularly curved, the surgical path is a three-dimensional curve with complex curvature. In order to fit the motion trajectory to the surgical path during the craniotomy performed by the robot-assisted surgeon, this paper realizes the trajectory planning of the surgical robot in Cartesian space by establishing a cubic non-uniform rational basis spline (NURBS) curve model based on the isosceles difference linear approximation method. Firstly, the key points of the surgical path are extracted as type value points. Then the control points are back-calculated. Finally, the cubic NURBS curve model for fitting the surgical path is established. On this basis, the cubic NURBS curve is interpolated using the isosceles difference linear approximation method to provide reasonable cutting steps for the physician's hand-held robot milling. Finally, the experiments show that the cubic NURBS curve model can accurately fit a smooth surgical path after the defined type-valued point coordinates. The motion trajectory after interpolation with the isosine difference linear approximation method can ensure robot motion smoothly.