Modern‐day radiotherapy relies on highly sophisticated forms of image guidance in order to implement increasingly conformal treatment plans and achieve precise dose delivery. One of the most important goals of such image guidance is to delineate the clinical target volume from surrounding normal tissue during patient setup and dose delivery, thereby avoiding dependence on surrogates such as bony landmarks. In order to achieve this goal, it is necessary to integrate highly efficient imaging technology, capable of resolving soft‐tissue contrast at very low doses, within the treatment setup. In this paper we report on the development of one such modality, which comprises a nonoptimized, prototype electronic portal imaging device (EPID) based on a thick, segmented crystalline CsI(Tl) detector incorporated into an indirect‐detection active matrix flat panel imager (AMFPI). The segmented detector consists of a matrix of optically isolated, crystalline CsI(Tl) elements spaced at pitch. The detector was coupled to an indirect detection‐based active matrix array having a pixel pitch of , with each detector element registered to array pixels. The performance of the prototype imager was evaluated under very low‐dose radiotherapy conditions and compared to that of a conventional megavoltage AMFPI based on a Lanex Fast‐B phosphor screen. Detailed quantitative measurements were performed in order to determine the x‐ray sensitivity, modulation transfer function, noise power spectrum, and detective quantum efficiency (DQE). In addition, images of a contrast‐detail phantom and an anthropomorphic head phantom were also acquired. The prototype imager exhibited approximately 22 times higher zero‐frequency DQE compared to that of the conventional AMFPI . The measured zero‐frequency DQE was found to be lower than theoretical upper limits calculated from Monte Carlo simulations, which were based solely on the x‐ray energy absorbed in the detector—indicating the presence of optical Swank noise. Moreover, due to the nonoptimized nature of this prototype, the spatial resolution was observed to be significantly lower than theoretical expectations. Nevertheless, due to its high quantum efficiency , the prototype imager exhibited significantly higher DQE than that of the conventional AMFPI across all spatial frequencies. In addition, the frequency‐dependent DQE was observed to be relatively invariant with respect to the amount of incident radiation, indicating x‐ray quantum limited behavior. Images of the contrast‐detail phantom and the head phantom obtained using the prototype system exhibit good visualization of relatively large, low‐contrast features, and appear significantly less noisy compared to similar images from a conventional AMFPI. Finally, Monte Carlo‐based theoretical calculations indicate that, with proper optimization, further, significant improvements in the DQE performance of such imagers could be achieved. It is strongly anticipated that the realization of optimized versions of such very high‐DQE EPIDs would enable megavoltage projection imaging at very low doses, and tomographic imaging from a “beam's eye view” at clinically acceptable doses.