Current evidence emerging from both human and animal models confirms that high-salt diet consumption over a period modulates the gut ecology and subsequently accelerates the development of the pathophysiology of many metabolic diseases. The knowledge of short-term intake of a high-salt diet (HSD) on gut microbiota and their role in the progression of metabolic pathogenesis and the consequence of a typical course of common antibiotics in this condition has yet not been investigated. The present study elicited this knowledge gap by studying how the gut microbiota profile changes in mice receiving HSD for a short period followed by Amoxicillin treatment on these mice in the last week to mimic a typical treatment course of antibiotics. In this study, we provided a standard chow diet (CD) and HSD for 3 weeks, and a subset of these mice on both diets received antibiotic therapy with Amoxicillin in the 3rd week. We measured the body weight of mice for 3 weeks. After 21 days, all animals were euthanised and subjected to a thorough examination for haemato-biochemical, histopathological, and 16S rRNA sequencing, followed by bioinformatics analysis to determine any changes in gut microbiota ecology. HSD exposure in mice for short duration even leads to a significant difference in the gut ecology with enrichment of specific gut microbiota crucially linked to developing the pathophysiological features of metabolic disease-related inflammation. In addition, HSD treatment showed a negative impact on haemato-biochemical parameters. However, Amoxicillin treatment in HSD-fed mice restored the blood-biochemical markers near to control values and reshaped gut microbiota known for improving the pathophysiological attributes of metabolic disease related inflammation. This study also observed minimal and insignificant pathological changes in the heart, liver, and kidney in HSD-fed mice.