The global health challenge of antibiotic resistance calls for the development of innovative medicines. Combination treatment with licensed antibiotics using inhibitors that target intrinsic resistance systems offers a different approach to creating effective therapies. Since the mid-1940s, when the first aminoglycoside antibiotic, streptomycin, was introduced into clinical practice, aminoglycoside antibiotics, or AGAs, have been used extensively to treat clinical bacterial infections. However, the bacterial resistance to aminoglycoside is increasing day by day. The overexpression of the active efflux pump gene, methylation of the 16S ribosomal RNA subunit, and alteration of aminoglycoside-modifying enzymes are the causes of bacterial resistance to AGAs. These modifications result in altered AGA structures and reduced drug concentrations in the bacteria. AGAs are difficult and time-consuming to develop because of their adverse effects and bacterial resistance. The antibacterial activity of the combination was found to be not only better than that of AGAs alone but also reduced the dosage of antibiotics, hence lowering the occurrence of side effects. This is because bacterial resistance may emerge shortly after application in practical practice. The development that is of special relevance is a recent one in which AGAs and other drugs have been combined to create a synergistic antibacterial action that provides a fresh strategy to counteract bacterial resistance to AGAs.