Zebrafish is a valuable model for antiangiogenic drug testing. We hypothesized that the efficacy of antiangiogenic compounds might vary in hypoxic tissue environments compared to normal tissue. To explore this, we established a chemically induced zebrafish model using DMOG, which inhibits prolyl hydroxylases, and a genetic model by knocking out vhl gene via CRISPR/Cas9 to activate hypoxia signaling. In wild-type larvae, the antiangiogenic drug sorafenib inhibited blood vessel growth. However, in the DMOG model and vhl-/- model, no inhibition occurred in sub-intestinal vessel (SIV) upon sorafenib treatment. Also, gene expression analysis showed that the DMOG induced hypoxia had 20-fold increase in phd3 expression, a marker for hypoxia signaling activation, which rose to 65-fold and 280-fold with sorafenib treatment at the concentration 0.1 μM and 0.2 μM, respectively. In the vhl-/- model phd3 expression was found to be increased to 220-fold and reaching up to 400-fold with sorafenib treatment. This increased activation of hypoxia signaling elevated the proangiogenic factors like vegfaa, vegfab and vegfd, which might have protected the SIV region from sorafenib treatment in hypoxic models. This confirms that the hypoxia zebrafish models gained resistance against chemotherapeutic drugs by increasing the cellular hypoxia levels. Thus, our zebrafish model for hypoxia provides evidence that the efficacy of chemotherapy for cancer significantly depends on hypoxic microenvironment.