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Chemical investigation of the root of Zanthoxylum paracanthum afforded 1 new alkamide derivative, (2E,4E)-6-oxo-N-isobutyldeca-2,4-dienamide (1) together with 10 known congeners including one phenolic amide (2), four benzophenanthridines (3 − 6), three indolonaphthyridines (7 − 9) and two lignans (10 and 11). Their structures were elucidated by a combination of spectroscopic and spectrometric data. Using resazurin reduction assay, the crude extract (10 µg/mL) and isolates (10 µM) were screened for their cytotoxic activities against the drug-sensitive (CCRF-CEM) leukemia cell line and its multidrug-resistant counterpart (CEM/ADR5000). Compounds 3, 4 and 6 showed cytotoxicity against CCRF-CEM with IC50 values of 2.00 ± 0.33, 2.31 ± 0.20 and 0.11 ± 0.04 µM, respectively. Only compound 6 exhibited strong cytotoxic activity against CEM/ADR5000 with an IC50 value of 2.34 ± 0.34 µM in comparison with the standard drug doxorubicin which showed IC50 values of 0.01 ± 0.14 (CCRF-CEM) and 26.78 ± 3.30 µM (CEM/ADR5000).