The reliability of high clearance boom sprayer chassis was studied by simulation and experiment. The stress distribution and the weak positions of the chassis were simulated by software ANSYS. According to the finite element results, the relation equations between the load of testing points and weak positions were obtained. The load spectrum measurement experiments of spray machine chassis were carried out under typical using conditions. In data statistics processing, the rain-flow method was adopted. By means of the Miner’s rule, the cumulative damages of weak positions of the chassis under various typical conditions were calculated. According to the actual use of the spray machine, the real life of the chassis was calculated by a weighted average of the damage under various typical conditions. The research method and the analysis results can provide guidance for reliability design of agricultural machinery.