Performance analysis of flexible manufacturing systems has received substantial research attention. Most of the studies focus on steady-state behavior. The transient performance, which is critical for system operation, control, and improvement, is less investigated. No analytical method is available to evaluate the transients in flexible lines with unreliable machines, finite buffers, and setup times. In this article, an analytical model is introduced to study the transient performance of multiproduct serial lines with Bernoulli reliability machines and nonnegligible setups during changeovers. To reduce the state-space dimension, an approximation method is introduced to evaluate the performance in two-machine lines, where the sequence of multiple part types in the inventory is approximated by the ratio of product mix. Such an approximation method leads to high precision of production rate estimation. Then, for longer lines, the analysis approach in two-machine lines is used as a building block in an iterative aggregation procedure. Numerical experiments show that the iteration procedure is convergent and results in an acceptable accuracy in performance evaluation. In addition, system properties, such as monotonicity and reversibility, are investigated. Note to Practitioners-Manufacturing systems become more and more flexible, where multiple types of products are made on the same production lines. Although significant efforts have been devoted to studying flexible manufacturing systems (FMSs), most of the research contribute to the steady-state analysis. However, the transient performance is of critical importance for control and improvement of flexible systems, particularly, when the system's setup times cannot be ignored. Therefore, in this article, an analytical method using approximation and aggregation procedures is introduced to evaluate the performance of flexible serial lines with Bernoulli machines and setups. Applying such a method, a long serial line is first decomposed into overlapped two-machine lines and then an iteration procedure is used backward and forward to estimate the line performance. Moreover, even in two-machine lines, the part sequence is approximated by the distribution of part types to reduce computation intensity. Using such a method, the system performance of long multiproduct Bernoulli lines with setups can be evaluated efficiently with an acceptable accuracy, which provides production engineers and managers an effective tool to study the transient performance of FMSs, and design real-time production control and improvement strategies.