Organisms are exposed to multiple toxicants in their surroundings in the increasingly contaminated complex environment. Such toxic exposures are observed to trigger complex biological responses that might or might not be identical to the responses elicited by individual exposures of the same toxicants. Two notable water contaminants, fluoride (F) and arsenic (As) are present worldwide and pose threat to organisms. These contaminants are consumed via contaminated water, drugs, toothpastes, cosmetics etc. Symbiotic microbiota dwelling in the gastrointestinal tract, are the key modulators of host health. Number of reports have concluded that F and As can alter the gut bacterial homeostasis, leading to the deterioration of host health. All the vital bodily systems including digestive, cardiovascular, nervous, reproductive and renal, are getting affected due to the alteration of gut bacteria. This scenario surely hints towards a complex association between toxicants, gut microbiota and host health. Taking into consideration, the present review intends to focus on individual and combined effects of F and As on the perturbation of gut bacteria of different organisms with special emphasis on the effect on human health.Graphical Abstract: