Proteins fused to HaloTag, an engineered haloalkane dehalogenase, can be depleted by a heterobifunctional degrader compound HaloPROTAC3. The binding of HaloPROTAC3 to both the HaloTag and the E3 ligase von Hippel-Lindau (VHL) brings them into proximity and mediates the degradation of the HaloTag fusion proteins. Here, we generated a colon cancer cell line HCT116 expressing HaloTag fused to the RNA-binding protein IGF2BP3 to study its function. HaloPROTAC3 treatment depleted 75% of HaloTag-IGF2BP3 in 5 h. Transcriptomics revealed that HaloPROTAC3 treatment resulted in the destabilization of IGF2BP3 target mRNAs and activated the unfolded protein response (UPR). Surprisingly, we found that HaloPROTAC3 results in UPR activation in nonengineered mammalian cells. Our data demonstrate that HaloPROTAC3 causes mild endoplasmic reticulum stress independent of IGF2BP3 function and shall guide future studies using the HaloPROTAC3 protein depletion strategy.