Obesity adversely impacts millions of American adults by predisposing them to significant health risks and further complications. Obesity is differentiated into two groups: metabolically healthy and metabolically unhealthy. In contrast to metabolically healthy counterparts, obese individuals who are metabolically unhealthy display hallmark symptoms of metabolic syndrome (e.g., hypertension, dyslipidemia, hyperglycemia, abdominal obesity). Gastroesophageal reflux disease (GERD) commonly occurs in all obese populations, as do poor dietary habits. Proton-pump inhibitors (PPIs), due to their wide availability, are most often used to treat GERD-related heartburn and other symptoms. Here, we review the evidence on how poor diet as well as short- and long-term use of PPIs adversely affect the gastrointestinal microbiota to cause dysbiosis. Key components of dysbiosis-induced metabolically unhealthy obesity (MUO) associated with PPI use include “leaky gut,” systemic low-grade inflammation, and reduced amounts of short-chain fatty acids (SCFAs) such as butyrate that promote metabolic health. The benefit of using probiotics to mitigate PPI-induced dysbiosis and MUO is also discussed.