The aim of this research was to investigated the effects of triptolide (TP) and its liposome nanoparticles (TP-LNP) on the apoptosis of multiple myeloma (MM) cells induced by Bortezomi. The encapsulation rate (ER), drug loading (DL), particle size (PS), and Zeta potential characteristics of the TP-LNP were evaluated. MMT assay was employed to detect the inhibitory effect of TP single agent and TP-LNP on proliferation of MM cells. MM cells were enrolled into a control group (Ctrl group, no intervention), a Bortezomi group (75 nM Bortezomi intervention 12 h), a Bortezomi +TP group (Bortezomi combined with TP monotherapy), and a Bortezomi+TP-LNP group (Bortezomi combined with TP-LNP). CCK-8, flow cytometry, and Western blot were utilized to detect the cell survival rate (SR), apoptosis, and MAPK/ERK pathway related protein, respectively. The results revealed that the shape of TP-LNP was similar to circular and uniformly distributed. Its average PS was (181.2±6.3) nm, the average Zeta potential was −29.15 mV, the average ER was 82.1%, and the average DL was 1.09%. When the drug concentration was 100 nmol/L, the inhibition rates of cell proliferation of TP and TP-LNP were (66.8±0.5)% and (81.4±0.6)%, respectively; and their median inhibitory concentrations (MICs) after 72 h were (89.5±1.8) nmol/L and (55.3±2.2) nmol/L, respectively. Based on the Ctrl group, the SRs in the Bortezomi, Bortezomi+TP, and Bortezomi+TP-LNP groups were decreased obviously, while the apoptosis rates were increased, and the comparisons herein exhibited great differences with P <0.05. The SR in the Bortezomi+TP-LNP group was the lowest and the apoptosis rate was the highest, showing great differences among the three groups (P < 0.05). Based on the Ctrl group, the expressions of P-P38 and P-ErK in the Bortezomi, Bortezomi+TP, and Bortezomi+TP-LNP groups were decreased (P <0.05). The levels of P-P38 and P-Erk in the Bortezomi+TP-LNP group were the lowest, and the differences in those in this group and the Bortezomi and the Bortezomi+TP groups statistically great (P <0.05). TP-LNP could inhibit the activation of MAPK/ERK pathway, enhance the apoptosis of MM cells induced by Bortezomi, and inhibit the cell proliferation.