Methyl farnesoate (MF) is an important hormone controlling crustacean growth. Our previous study has demonstrated that the treatment of juvenile hormone antagonist KK-42 can accelerate growth of Penaeus schmitti. The expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), a key enzyme of MF precursor production, was assayed using real-time PCR, and hemolymph MF titer was determined by high-performance liquid chromatography. Shrimp, 3.5–5.0 cm long, were soaked for 1 min in KK-42 solution at a concentration of 1.95 × 10−4 mol/L or in the solution without KK-42 and then cultured in normal way. Results showed that the highest level of hmgr transcript occurred in mandibular organ (MO). Administration of KK-42 resulted in HMGR expression to be notably depressed in the MO, even reduced by 80.2% (P < 0.01) and 90.7% (P < 0.01) on Day 1 and Day 7, respectively. The MF level showed a decline trend in KK-42 treatment compared to that of corresponding control group. Our present study demonstrates that treatment of KK-42 significantly inhibits HMGR expression in different tissues especially in the MO, which is likely one of KK-42 growth-promoting mechanisms on P. schmitti.