When provided individually, both the serotonin (5-HT(1A))-receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and environmental enrichment (EE) enhance behavioral outcome and reduce histopathology after experimental traumatic brain injury (TBI). The aim of this study was to determine whether combining these therapies would yield greater benefit than either used alone. Anesthetized adult male rats received a cortical impact or sham injury and then were randomly assigned to enriched or standard (STD) housing, where either 8-OH-DPAT (0.1 mg/kg) or vehicle (1.0 mL/kg) was administered intraperitoneally once daily for 3 weeks. Motor and cognitive assessments were conducted on post-injury days 1-5 and 14-19, respectively. CA1/CA3 neurons and choline acetyltransferase-positive (ChAT(+)) medial septal cells were quantified at 3 weeks. 8-OH-DPAT and EE attenuated CA3 and ChAT(+) cell loss. Both therapies also enhanced motor recovery, acquisition of spatial learning, and memory retention, as verified by reduced times to traverse the beam and to locate an escape platform in the water maze, and a greater percentage of time spent searching in the target quadrant during a probe trial in the TBI + STD + 8-OH-DPAT, TBI + EE + 8-OH-DPAT, and TBI + EE + vehicle groups versus the TBI + STD + vehicle group (p ≤ 0.0016). No statistical distinctions were revealed between the TBI + EE + 8-OH-DPAT and TBI + EE + vehicle groups in functional outcome or CA1/CA3 cell survival, but there were significantly more ChAT(+) cells in the former (p = 0.003). These data suggest that a combined therapeutic regimen of 8-OH-DPAT and EE reduces TBI-induced ChAT(+) cell loss, but does not enhance hippocampal cell survival or neurobehavioral performance beyond that of either treatment alone. The findings underscore the complexity of combinational therapies and of elucidating potential targets for TBI.