Background: Esophageal squamous cell carcinoma (ESCC) remains highly aggressive and continues to limit clinical treatment for substantial cancer-associated morbidity and mortality worldwide. Despite advances in therapeutic interventions the lack of effective molecularly targeted treatments continues to restrict clinical management beyond conventional chemotherapy and radiotherapy. Among these therapeutic targets the ribosomal S6 kinase 4 (RSK4) has gained considerable attention because of its critical involvement in ESCC progression, survival and proliferation, suggesting its potential as a potential target for anticancer drug development. Methods: A series of thiazole-clubbed pyrimidine linked hydrazone hybrids (1–14) were synthesized via 4-aminothiazole-5-carbohydrazide functionalized intermediates and fully characterized and evaluated for their inhibitory activity against RSK4. Results: Biological assessment demonstrated that the synthesized analogues exhibited remarkable potency, with IC₅₀ values between 15.32 ± 1.35 and 54.61 ± 2.17 nM compared with the reference inhibitor BI-D1870 (IC₅₀ = 33.16 ± 1.34 nM). Among the evaluated compounds, 2, 8, 9, 13 and 14 emerged as the most potent candidates and showed pronounced activity towards RSK4. For further insights into the molecular basis of their activity the lead candidates were subjected to computational investigations, such as molecular docking, molecular dynamics simulations, in silico ADMET and ProTox-3.0 characterization. The computational analyses provided structural and pharmacological insights into experimentally observed RSK4 inhibitory activity, like predicted interactions, stability dynamically and preliminary ADMET/toxicity characteristics. This study supports the need for further optimization and experimental validation of the identified RSK4 active lead candidates. Conclusions: These findings highlight the thiazole-clubbed pyrimidine-linked hydrazone scaffold as a potential chemotype for promising scaffolds targeting RSK4 lead discovery, and the identified candidates warrant further investigation into ESCC cellular models to establish anticancer efficacy and pathway-level activity.