Bladder cancer has a high recurrence rate, which indicates that the therapeutic effects of advanced bladder cancers are still limited. In this study, we combined vorinostat and cyproheptadine as a new treatment for bladder cancer. When combining the two drugs, an additive to synergistic effect is discovered. Furthermore, we modified the structure of vorinostat using cyproheptadine tricyclic ring to get compounds 8 C and O8C, which keep HDAC inhibitory activity and have IC₅₀ lower than 10 μM in 5637, BFTC 905, and MB49 cells. In in vitro assay, vorinostat, 8 C and O8C increased the percentage of cell cycle in G2/M in 5637, while G0/G1 arrest in BFTC 905. Apoptosis was seen in 5637 and slightly in BFTC 905 by the Annexin V-PI staining assay, and a minor rescued cell viability after Z-VAD-FMK pretreatment in 5637. 8 C and O8C slightly decreased MMP, and increased ROS levels. Among different ROS scavenger treatments, only N-acetyl-L-cysteine shows a minor viability rescue, indicating ROS may not take an important role in 8C- and O8C-induced cell death. In the in vivo assay, mice underwent intraperitoneal injection of 8 C, delaying tumor growth compared to cyproheptadine, vorinostat, and O8C individually. Because the water solubility of 8 C is not good, we use its salt form 8C-HCl for further in vivo study. Mice underwent gavage of 8C-HCl, which resulted in delaying tumor growth. In conclusion, 8 C and 8C-HCl, from structure modification of vorinostat by cyproheptadine tricyclic ring, enhance tumor suppressive effect in vitro and in vivo.