Acute human alpha-herpesvirus 1 (HSV-1) infection culminates in a latent infection of neurons in trigeminal ganglia (TG) and the central nervous system. Following infection of mucosal epithelial cells, certain neurons survive infection and life-long latency is established. Periodically, stressful stimuli trigger reactivation from latency, which result in virus shedding, transmission to other people, and, occasionally, recurrent disease. The glucocorticoid receptor (GR) and Krüppel-like factor 15 (KLF15) comprise a feed-forward transcriptional loop that cooperatively transactivate key HSV-1 promoters that drive expression of infected cell protein 0 (ICP0), ICP4, and ICP27. Silencing KLF15 significantly reduces HSV-1 replication in cultured mouse neuroblastoma cells. Consequently, we hypothesized that KLF15 mediates certain aspects of reactivation from latency. To test this hypothesis, we compared HSV-1 replication in KLF15 mice versus wild-type (wt) parental C57BL/6 mice. Virus shedding during acute infection was reduced in KLF15 mice. Male KLF15 mice shed higher titers of virus during late stages of reactivation from latency compared to KLF15 females and wt mice regardless of sex. At 15 d after explant-induced reactivation, virus shedding was higher in male KLF15 mice relative to wt mice and female KLF15 mice. These studies confirm KLF15 expression enhances viral replication during acute infection and reactivation from latency.