Biological aging is accompanied by a chronic pro-inflammatory state that may facilitate losses in hippocampal-dependent mnemonic discrimination. Aerobic exercise training promotes adaptations that include improved immune competency, higher cardiorespiratory fitness, and maintenance of hippocampal function. However, it is poorly understood whether, in active older adults, baseline immune cell profiles and cardiorespiratory fitness are possible mechanisms that facilitate the long-term benefits to hippocampal dependent mnemonic discrimination performance. This within-subjects study with counterbalanced conditions aimed to investigate whether baseline monocyte polarization and cardiorespiratory fitness influenced performance in the mnemonic similarity task (MST) and related Lure Discrimination Index (LDI) score after an acute bout of exercise. Twenty-one active older adults (M = 68 ± 5 yrs) underwent baseline testing in which blood samples were collected and cardiorespiratory fitness measured. Participants then returned and completed a seated rest or moderate intensity aerobic exercise condition in which the MST was proctored prior to and 5 min after each condition. A linear mixed effects model was used in which Participant ID was a random effect and Condition (rest v. exercise), Time (pre- v post-), and order were fixed main effects. Simple linear regression models were used to determine the variance accounted for by monocyte phenotypes and cardiorespiratory fitness for LDI scores post-condition. Post-rest LDI scores were significantly lower than post-exercise LDI scores (t(20) = -2.65, p < 0.02, d = -0.57). Intermediate monocytes were significant predictors of the change in pre- to post-exercise LDI scores (F(1, 19) = 6.03, p = 0.024, R2 = 0.24) and cardiorespiratory fitness was a significant predictor of the difference between post-condition LDI scores (F(1, 19) = 6.71, p = 0.018, R2 = 0.26). Our results suggest baseline cardiorespiratory fitness and intermediate monocytes may relate to the integrity of hippocampal-dependent mnemonic discrimination performance, and possibly the degree of responsiveness to aerobic exercise interventions.