The accurate reconstruction of cone-beam computed tomography (CBCT) from sparse projections is one of the most important areas for study. The compressed sensing theory has been widely employed in the sparse reconstruction of CBCT. However, the total variation (TV) approach solely uses information from the i-coordinate, j-coordinate, and k-coordinate gradients to reconstruct the CBCT image.It is well recognized that the CBCT image can be reconstructed more accurately with more gradient information from different directions. Thus, this study introduces a novel approach, named the new multi-gradient direction total variation minimization method. The method uses gradient information from the ij-coordinate, ik-coordinate, and jk-coordinate directions to reconstruct CBCT images, which incorporates nine different types of gradient information from nine directions.This study assessed the efficacy of the proposed methodology using under-sampled projections from four different experiments, including two digital phantoms, one patient's head dataset, and one physical phantom dataset. The results indicated that the proposed method achieved the lowest RMSE index and the highest SSIM index. Meanwhile, we compared the voxel intensity curves of the reconstructed images to assess the edge structure preservation. Among the various methods compared, the curves generated by the proposed method exhibited the highest level of consistency with the gold standard image curves.In summary, the proposed method showed significant potential in enhancing the quality and accuracy of CBCT image reconstruction.Copyright © 2024 Copyright: © 2024 Journal of Cancer Research and Therapeutics.