Small bowel adenocarcinomas (SBAs) are rare malignant tumors with a high mortality rate, and their molecular characteristics are still largely unexplored. Here we performed single-cell RNA sequencing for tumor samples from 12 SBA patients and predicted drug candidates for SBA. We identified four prevalent subtypes of malignant cells with distinct signatures including cell cycle program, mitochondria program, metabolism program and epithelial-mesenchymal transition (EMT) program. The progression relationships of these four subtypes of malignant cells were also revealed, which started from the cell cycle program, through the mitochondria program and then progressing into either the metabolism program or the EMT program. Importantly, ligand-receptor interaction pairs were found to be specifically enriched in pairs of EMT-program malignant cells and highly exhausted CD8+ T cells, suggesting that cancer cell subpopulations with EMT features may contribute most to the exhaustion of T cells. We also showed that the duodenal subtype of SBA exhibited molecular features more similar to gastric cancer whereas jejunal subtype of SBA more similar to colorectal cancer. Especially, we predicted specific drugs for SBA based on differential gene expression signatures between malignant cells and normal epithelial cells of SBA, and verified more potent inhibitory effects of volasertib and tozasertib for SBA cancer cells than conventional drugs of SBA at the same concentration, which provides new clues for treatments of SBA. In summary, our study provides a blueprint of the molecular signatures of both tumor cells and tumor microenvironment cells in SBA and reveals potential targets and drug candidates for its clinical treatments.