Tuberculosis (TB) remains a global health problem, and is the leading cause of death from an infectious disease. A crucial step in the treatment of tuberculosis is screening high risk populations and the early detection of the disease, with chest x-ray (CXR) imaging being the most widely-used imaging modality. As such, there has been significant recent interest in artificial intelligence-based TB screening solutions for use in resource-limited scenarios where there is a lack of trained healthcare workers with expertise in CXR interpretation. Motivated by this pressing need and the recent recommendation by the World Health Organization (WHO) for the use of computer-aided diagnosis of TB in place of a human reader, we introduce TB-Net, a self-attention deep convolutional neural network tailored for TB case screening. We used CXR data from a multi-national patient cohort to train and test our models. A machine-driven design exploration approach leveraging generative synthesis was used to build a highly customized deep neural network architecture with attention condensers. We conducted an explainability-driven performance validation process to validate TB-Net’s decision-making behavior. Experiments on CXR data from a multi-national patient cohort showed that the proposed TB-Net is able to achieve accuracy/sensitivity/specificity of 99.86/100.0/99.71%. Radiologist validation was conducted on select cases by two board-certified radiologists with over 10 and 19 years of experience, respectively, and showed consistency between radiologist interpretation and critical factors leveraged by TB-Net for TB case detection for the case where radiologists identified anomalies. The proposed TB-Net not only achieves high tuberculosis case detection performance in terms of sensitivity and specificity, but also leverages clinically relevant critical factors in its decision making process. While not a production-ready solution, we hope that the open-source release of TB-Net as part of the COVID-Net initiative will support researchers, clinicians, and citizen data scientists in advancing this field in the fight against this global public health crisis.