Prebiotics are substrates selectively utilized by host microorganisms conferring a health benefit. The effects of prebiotics on the gut microbiome of individuals with inflammatory processes need further investigations. The purpose of this study was to evaluate the effects of prebiotics on the gastrointestinal microbiome of individuals with some types of inflammatory conditions. Randomized controlled clinical trials (RCTs) evaluating the effects of different prebiotics on the gut microbiome were included. A systematic review of the literature including searches in PubMed/MEDLINE, EMBASE, Cochrane Library, Web of Science, and Scopus databases was performed until 23 March 2023. The risk of bias was assessed using the Cochrane Collaboration's criteria. Qualitative data was tabulated to facilitate comparisons and represented in the form of descriptive statistics and summary tables. Thirty trials, ranging from 12 to 135 patients, were included. The most commonly used prebiotic type was inulin-type fructans, and the treatment duration ranged from 1 to 36 weeks. The majority of the trials investigated the gut microbiome using 16 s rRNA gene sequencing on the Illumina Miseq platform. In general, prebiotic therapy exerted positive effects on inflammatory conditions. An increase in Bifidobacterium genus was the most common shift in bacterial composition observed. Within the limits of this systematic review, it can be suggested that prebiotic therapy presents the potential to favorably modulate the gastrointestinal microbiome of individuals with different types of inflammatory conditions. © 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.