Receptor tyrosine kinase (RTK) signaling is frequently dysregulated in hepatocellular carcinoma (HCC), but the activity of individual RTKs can vary substantially among tumor cells. In this study, we compared RTK signaling profiles in Hep3B and Huh-7 HCC cells and investigated the pharmacological activity of BJ-2454, a newly synthesized 5-hydroxy-7-azaoxindole derivative. RTK profiling revealed different patterns of receptor activation between the two cell lines. EGFR showed the strongest activation in both cell lines, whereas IGF-1R and InsR signaling was prominent in Hep3B but low in Huh-7, where AXL was the second most activated RTK. BJ-2454 inhibited multiple RTKs and showed particularly potent activity against TrkC. At the cellular level, BJ-2454 modulated multiple oncogenic signaling pathways, including Raf–ERK and JAK2–STAT3 signaling, and reduced prosurvival protein expression. These effects were accompanied by antiproliferative activity that differed between the two HCC cell lines. BJ-2454 also enhances the antiproliferative effects of established kinase inhibitors, including sorafenib. Furthermore, BJ-2454 suppressed tumor growth in an HCC xenograft model, and combined treatment with sorafenib resulted in greater antitumor activity than either agent alone. Together, these findings demonstrate that BJ-2454 modulates multiple RTK-associated signaling pathways in HCC and support further investigation of its potential in combination with kinase-directed therapy.