Background The gut-brain axis involves bidirectional communication between the gut-microbiota and central nervous system. This study aimed to investigate whether probiotics and/or prebiotics, known as Microbiome-targeted Therapies (MTTs), improve cognition and prevent postoperative cognitive dysfunction (POCD). Methods Relevant animal and human studies were identified using a systematic database search (PubMed, EMBASE, Cochrane Library, and Web of Science), focusing on the effects of MTTs on inflammation, perioperative and non-perioperative cognitive impairment. Screening and data extraction were conducted by two independent reviewers. The Risk of bias was assessed using the SYRCLE’s risk of bias tool for animal studies. The revised Cochrane risk of bias tool (RoB 2) was used for human studies. Results A total of 24 articles were selected; 16 of these involved animal studies, and 8 described studies in humans. In these papers, the use of MTTs consistently resulted in decreased inflammation in perioperative and non-perioperative settings. Out of 16 animal studies, 5 studies (2 associated with delirium and 3 studies related to POCD) were conducted in a perioperative setting. MTTs improved perioperative cognitive behavior and reduced inflammation in all 5 animal studies. Eleven animal studies were conducted in a non-perioperative setting. In all of these studies, MTTs showed improvement in learning and memory function. MTTs showed a positive effect on levels of pro-inflammatory cytokines and biomarkers related to cognitive function. Among the 8 human studies, only one study examined the effects of perioperative MTTs on cognitive function. This study showed a reduced incidence of POCD along with improved cognitive function. Of the remaining 7 studies, 6 suggested that MTTs improved behavioral test results and cognition in non-perioperative environments. One study failed to show any significant differences in memory, biomarkers of inflammation, or oxidative factors. Conclusion In the studies we examined, most showed that MTTs decrease inflammation by down-regulating inflammatory cytokines and oxidative stress in both perioperative and non-perioperative settings. In general, MTTs also seem to have a positive effect on cognition through neural, immune, endocrine, and metabolic pathways. However, these effects have not yet resulted in a consensus regarding preventative strategies or treatments. Based on these current research results, MTTs could be a potential new preventative strategy for cognitive impairment after surgery.