Background: EHMT2 (G9a) is a key epigenetic regulator frequently overexpressed in various cancers. While several inhibitors exist, their in vivo efficacy and pharmacokinetic (PK) properties remain poorly characterized. Methods: We compared the biochemical, cellular, and PK profiles of two widely used EHMT2 inhibitors, BIX-01294 and UNC0642, and evaluated their antitumor efficacy in xenograft and syngeneic mouse models. Results: Despite a higher enzymatic potency of UNC0642 (IC₅₀ = 0.277 μM) compared to BIX-01294 (IC₅₀ = 1.983 μM), BIX-01294 demonstrated superior cellular growth inhibition and higher intracellular accumulation. PK analysis further revealed that BIX-01294 achieved higher systemic exposure (AUC) and a wider therapeutic window via intraperitoneal administration, whereas UNC0642 exhibited dose-limiting lethality above 8 mg/kg. In HT-29 and MIA PaCa-2 xenografts, BIX-01294 (40 mg/kg) achieved up to 70.6% tumor growth inhibition (TGI), substantially surpassing UNC0642. Furthermore, in MC38 syngeneic models, a BIX-01294/anti-PD-L1 antibody combination produced an additive effect. This combination markedly increased the number of tumor-infiltrating CD8α⁺ T cells and NK1.1⁺ cells. Conclusions: These results suggest that BIX-01294 is more effective in vivo than UNC0642 due to its favorable PK profile and superior cellular uptake. Our findings support the further development of EHMT2 inhibitors as potent partners for immune checkpoint blockades.