This study aims to explore the pharmacological mechanism of Brucea javanica (BJ) in treating multiple myeloma (MM) through network pharmacology and validate this mechanism via in vitro experiments. Active pharmaceutical ingredients (APIs) of BJ and their potential targets were identified, along with MM-related targets. By plotting protein-protein interaction (PPI) networks, hub genes responsible for BJ in treating MM were identified and subjected to molecular docking. In MM cell lines H929 and U266, regulatory effects of BJ and luteolin (the major compound of BJ) on the behaviors of MM cells were examined. BJ extract exhibited dose-dependent cytotoxicity against MM cells, with IC values of 5.03 µL/mL (48 h) for H929, and 1.06 µL/mL (48 h) for U266. Network pharmacology identified 14 APIs and 11 hub genes, with molecular docking confirming strong binding affinity between luteolin and TNF (-8.001 kcal/mol). 48-hour luteolin treatment suppressed MM cell proliferation (IC: 84.73 µM for H929; 46.93 µM for U266), induced apoptosis (up to 53.03% and 9.22% late apoptosis in H929 and U266 at 80 µM), and arrested cell cycle at G0/G1 phase. It downregulated TNF/NF-κB pathway components, reducing mRNA levels of TNF, IL-6, and NFKB1, and protein levels of p105, p50, and p65. TNF-α secretion decreased in luteolin-treated cells to 10.62% in H929 cells and 67.25% in U266 cells. This study demonstrates that BJ inhibits MM progression primarily via suppression of the TNF/NF-κB signaling pathway, with luteolin as a pivotal bioactive compound.