Growing evidence implicates the gut microbiome in brain health and disease. Since worldwide consumption of oral antibiotics continues to rise, it is imperative to understand how microbiome-depleting antibiotics affect cognition. We studied a murine model in which mice drank water containing an antibiotic cocktail (ABX group) or untreated water (CON group). Separate cohorts received butyrate, a key microbiome-derived metabolite, either in the presence (ABXBA group) or absence (BA group) of antibiotics. The four groups were tested at 4 weeks of treatment. We assessed hippocampus–related spatial cognition with the object place memory (OPM) and clockmaze tasks (PMC6568215), as well as recognition memory (novel object recognition task), anxiety-like behaviors (elevated plus maze, light-dark chamber, zero maze tasks), and motor learning (rotarod task). Mice were implanted with tetrode arrays to record CA1 place cells (PCs) and local field potentials (LFPs) in the dorsal hippocampus. Our results reveal that ABX mice show significant spatial impairment in the OPM and clockmaze tasks, but no significant changes to recognition memory, anxiety-like behaviors, and motor learning. Evaluation of PC dynamics during OPM shows that ABX–PCs have larger field sizes, lower spatial information, and altered remapping properties. Moreover, ABX place cells are unable to accurately reconstruct the path of the animal. Theta, beta, and gamma power are decreased, and theta-gamma coupling is lower in ABX mice. Remarkably, butyrate treatment protects mice from the hippocampus-based effects of ABX treatment as indicated by normal spatial cognition, place cell dynamics, and theta-gamma coupling in ABXBA mice