A side effect of cyclophosphamide (CP), an alkylating agent widely used to treat tumors and autoimmune disorders, is the alteration of male reproductive function. Yukmijihwang-tang (YJT) is a multi-herbal medicinal formula that has been used in traditional Asian medicine to treat male reproductive problems. In this study, we investigated the effects of YJT on CP-induced reproductive toxicities in rat testes. Eight-week-old male Wistar rats were divided into three groups: vehicle-treated (control), CP-treated and CP+YJT-treated groups. CP was administered for the first 7 days (20 mg/kg/day, p.o.), and YJT was administered for 56 days consecutively (1.0 g/kg/day, p.o.). The CP-treated group showed significant decreases in the weight of the testes, epididymal sperm count and sperm motility compared to the control group, while the CP+YJT-treated group had significant increases for these variables compared to the CP-treated group. The enhancement of lipid peroxidation by CP in the rat testes was reduced by YJT treatment. CP diminished the expression of cAMP-responsive element modulator (CREM), a transcription factor that is highly expressed in male germ cells and is crucial to post-meiotic germ cell differentiation. YJT restored CREM at both the mRNA and protein levels. These results suggest that YJT has a protective effect against CP-induced reproductive toxicities by inhibiting the increases in lipid peroxidation and enhancing CREM expression.