Antibiotic resistance is the most devastating of the global health problems worsened by the harmful practice of taking antibiotics when not necessary or when there is the case of antibiotics overdosing, as it leads to treatment failure and illness prolongation. In order to deal with this problem, the systems level analyses from genomic and proteomic levels were taken to elucidate the underlying molecular mechanism in the resistance of bacteria. This study proved that genetic mutations and protein overexpression were highly inter related in different bacterial species, Peculiarly, Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus. The highlights obtained encompass the determination of the resistance genes and the impairment of bacteria such as blaTEM, blaCTX-M, and gyrA, as well as the inappropriate proteins including AmpC β- lactamase, carbapenemase enzymes, and PBP2a. Some of the mechanisms bacteria use include the production of enzymes which help remove the antibiotics, the up-regulation of genes enhancing membrane permeability, and production of cells colonizing in the biofilm. Integration of omics profiling with clinical drug resistance characteristics foresee the potential for personalized medicine, which eventually may contribute to finding new drug candidates to cure this disease. Nevertheless, to combat the issue of antibiotic resistance, a holistic approach that comprises judicious utilization of antibiotics, good infection control practices, and the search for the next novel antimicrobial drug becomes necessary. The use of advancements in molecular biology and bioinformatics in our battle against antibiotic resistance would be a vital step in ensuring an adequate antibiotic arsenal for our future generations.