A multi-degree-of-freedom model is developed herein for prediction of response of an experimental cam-follower mechanism. Both transverse and axial flexibility of the follower rod and return spring, as well as transverse and torsional flexibility of the camshaft are included. The camshaft is assigned two rotational degrees of freedom, one at the cam and the other at the flywheel. The follower mass motion is also described by two degrees of freedom, one each in the axial and the transverse directions. The model takes into account the fluctuating camshaft angular speed and treats it as an input excitation. The governing second-order, nonlinear, nondimensionalized ordinary differential equations of motion, with time-periodic coefficients, are developed. In doing so, a comprehensive modeling of the kinematics of deformation of the flexible camshaft and follower system is considered, with the first inclusion of the transverse flexibility of the follower rod and return spring. With axial deflection, the transverse flexibility of the return spring gives rise to a phenomenon defined as moment stiffening. The transverse degree of freedom of the follower mass significantly influences the equivalent axial stiffness of the system. Its inclusion in the equation of motion yields a more accurate prediction of the experimental system behavior.