BACKGROUND: Quantitative accuracy is critical for expanding the role of cone beam CT (CBCT) imaging from target localization to quantitative treatment monitoring and plan adaptations in radiation therapy. Despite advances in CBCT image quality improvement methods, quantitative accuracy gap between CBCT and multi-detector CT (MDCT) remains. PURPOSE: In this work, a physics-driven approach was investigated that combined robust scatter rejection, raw data correction and iterative image reconstruction to further improve CBCT image quality and quantitative accuracy, referred to as quantitative CBCT (qCBCT). METHODS: QCBCT approach includes tungsten 2D antiscatter grid hardware, residual scatter correction with grid-based scatter sampling, image lag, and beam hardening correction for offset detector geometry linac-mounted CBCT. Images were reconstructed with iterative image reconstruction to reduce image noise. qCBCT was evaluated using a variety of phantoms to investigate the effect of object size and its composition on image quality, and image quality was benchmarked against clinical CBCT and gold standard MDCT images used for treatment planning. RESULTS: QCBCT provided statistically significant improvement in CT number accuracy and reduced image artifacts when compared to clinical CBCT images. When compared to gold standard MDCT, mean HU errors in qCBCT and clinical CBCT were 17 ± 9 and 38 ± 29 HU, respectively. Magnitude of phantom size dependent HU variations were comparable between MDCT and qCBCT images. With iterative reconstruction, contrast-to-noise ratio improved by 25% when compared to clinical CBCT protocols. CONCLUSIONS: Combination of novel scatter suppression techniques and other data correction methods in qCBCT provided CT number accuracy comparable to gold standard MDCT used for treatment planning. This approach may potentially improve CBCTs promise in fulfilling the tasks that demand high quantitative accuracy, such as online dose calculations and treatment response assessment, in image guided radiation therapy.