A radiopaque hydrogel-in-liposome (RHL) system was developed for micro-computed tomography (μCT) imaging of tumor tissue and simultaneous delivery of a cytotoxic agent. Iopamidol (IPD) and doxorubicin (DOX) were incorporated as the CT contrast and anti-cancer agents, respectively. The presence of a polyethylene glycol hydrogel core in the liposomes was confirmed via attenuated total reflectance Fourier transform infrared, proton nuclear magnetic resonance, and selective solvent extraction. Nano-sized (∼160 nm) spherical DOX/IPD-loaded RHLs with a narrow size distribution and negative zeta potential were successfully fabricated. The RHLs demonstrated enhanced cellular uptake of DOX in SCCVII cells compared to conventional radiopaque liposomes, likely due to clathrin-mediated endocytosis. Additionally, pH-dependent DOX release and reduced IPD leakage were observed. In vivo studies using SCCVII tumor-xenografted mice showed that RHLs exhibited improved CT contrast efficiency and anti-tumor efficacy, along with systemic biocompatibility, attributed to enhanced tumor-targeting properties. These findings suggest that the RHL system could serve as a promising nano-platform for tumor theranostics.