Obesity is associated with alterations in gut microbiome composition and disturbances in metabolic processes. The aim of the present study was to investigate the effects of probiotic supplementation, resistance training, and a Mediterranean high-protein diet on selected gut microbiome indices in obese men. This quasi-experimental study was conducted using a pretest–posttest design with a control group. Seventy obese men aged 25–45 years with a body mass index (BMI) of 30–35 kg/m² participated in this study. Participants were randomly assigned to seven groups (10 participants per group), including probiotic supplementation, resistance training, Mediterranean high-protein diet, two-intervention combinations, three-intervention combination, and control groups. The interventions were implemented for 12 weeks. Stool samples were collected before and after the intervention period, and the abundance of selected microbiome indices, including Akkermansia muciniphila, Bifidobacterium, Escherichia coli, Methanobacteriales, and Lactobacillus, was assessed. Data were analyzed using appropriate statistical methods, including mixed-design analysis of variance and Tukey’s post hoc test. The results showed that the investigated interventions were associated with significant changes in some selected gut microbiome indices. An increase in the abundance of Akkermansia muciniphila and Bifidobacterium and a decrease in Methanobacteriales were observed following the interventions. Changes in the abundance of Escherichia coli and Lactobacillus were also observed, indicating alterations in gut microbiome composition after the interventions. The findings suggest that exercise-based, dietary, and supplementation interventions may be associated with changes in selected gut microbiome indices in obese men. However, determining the causal relationship between these microbial changes and metabolic outcomes requires further investigation.