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This study was designed to evaluate the adaptive resistance of <i>Salmonella</i> Typhimurium under continuous sublethal selective pressure. <i>Salmonella</i> Typhimurium ATCC 19585 (ST^ATCC) and <i>S</i>. Typhimurium CCARM 8009 (ST^CCARM) were sequentially cultured for 3 days at 37 °C in trypticase soy broth containing 1/2 × MICs of cefotaxime (CEF^1/2), chloramphenicol (CHL^1/2), gentamicin (GEN^1/2), and polymyxin B (POL^1/2). The ST^ATCC and ST^CCARM exposed to CEF^1/2, CHL^1/2, GEN^1/2, and POL^1/2 were evaluated using antibiotic susceptibility, cross-resistance, and relative fitness. The susceptibilities of ST^ATCC exposed to GEN^1/2 and POL^1/2 were increased by a 2-fold (gentamicin) and 8-fold (polymyxin B) increase in minimum inhibitory concentration (MIC) values, respectively. The MIC values of ST^CCARM exposed to CEF^1/2, CHL^1/2, GEN^1/2, and POL^1/2 were increased by 4-fold (cefotaxime), 2-fold (chloramphenicol), 2-fold (gentamicin), and 8-fold (polymyxin B). The highest heterogeneous fractions were observed for the ST^ATCC exposed to CEF^1/2 (38%) and POL^1/2 (82%). The ST^CCARM exposed to GEN^1/2 was cross-resistant to cefotaxime (<i>p</i> < 0.05), chloramphenicol (<i>p</i> < 0.01), and polymyxin B (<i>p</i> < 0.05). The highest relative fitness levels were 0.92 and 0.96, respectively, in ST^ATCC exposed to CEF^1/2 and ST^CCARM exposed to POL^1/2. This study provides new insight into the fate of persistent cells and also guidance for antibiotic use.