The problem of peristaltic nanofluid flow in an asymmetric channel in the presence of the second-order slip boundary condition was investigated in this paper. To the best of the authors’ knowledge, this parameter was here incorporated for the first time in such field of a peristaltic flow. The system governing the current flow was found as a set of nonlinear partial differential equations in the stream function, pressure gradient, nanoparticle concentration, and temperature distribution. Therefore, this system has been successfully solved exactly via a very effective procedure. These exact solutions were then proved to reduce to well-known results in the absence of second slip which were published very recently in the literature. Effect of the second slip parameter on the present physical parameters was discussed through graphs and it was found that this type of slip is a very important one to predict the investigated physical model. Moreover, the variation of many physical parameters such as amplitudes of the lower and upper waves, phase difference on the temperature distribution, nanoparticle concentration, pressure rise, velocity, and pressure gradient were also discussed. Finally, the present results may be viewed as an optimal choice for their dependence on the exact solutions which are obtained due to the highly complex nonlinear system.