Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related mortality worldwide. Sorafenib is the standard first-line treatment for advanced HCC, but its efficacy is limited. Apatinib is a small-molecule tyrosine kinase inhibitor that has shown promising antitumor effects in gastric and non-small cell lung cancers in clinical trials, but there have been only a few studies reporting its anti-HCC effects in vitro and in HCC xenograft models. Hence, our present study systemically investigated and compared the antitumorigenic and antiangiogenic efficacy of apatinib and sorafenib in HCC in vitro and in vivo using multimodality molecular imaging, including bioluminescence imaging (BLI), bioluminescence tomography (BLT), fluorescence molecular imaging (FMI), and computed tomography angiography (CTA). Moreover, the safety and side effects of the two drugs were systemically evaluated. We found that apatinib showed a comparable therapeutic efficacy to sorafenib for the inhibition of HCC. The drug safety evaluation revealed that both of these drugs caused hypertension and mild liver and kidney damage. Sorafenib caused diarrhea, rash, and weight loss in mice, but these effects were not observed in mice treated with apatinib. In conclusion, apatinib has similar antitumorigenic and antiangiogenic efficacy as sorafenib in HCC with less toxicity. These findings may provide preclinical evidence supporting the potential application of apatinib for the treatment of HCC patients.