In view of the reports on co-selection of metal and antibiotic resistance, recently we have reported that increased cadmium accumulation in Salmonella Typhi Ty2 leads to increased antibiotic resistance. In continuation, the present study was carried to substantiate this association in clinical isolates. Interestingly, the levels of cadmium were found to be more in the clinical isolates which co-related with their antibiotic sensitivity/resistance pattern. On cadmium accumulation, antibiotic(s) sensitive isolates were rendered resistant and the resistant isolates were rendered more resistant as per their minimum inhibitory concentration(s). Further, after subjecting the pathogen to cadmium accumulation, alterations occurring in the cells were assessed. Transgenerational cadmium exposure led to changes in growth response, morphology, proteome, elevated antioxidants other than SOD, increased biofilm formation, decreased intracellular macrophage killing coupled with upregulation of genes encoding metallothionein and metal transporters. Thus, these results indicate that cadmium, if acquired from the environment, being non-degradable can exert a long-lasting selective pressure on Salmonella in the host which may display antibiotic resistance later on, as a result of co-selection. Therefore, appropriate strategies need to be developed to inhibit such an enduring pressure of heavy metals, as these represent one of the factors for the emerging antibiotic resistance in pathogens.