Around one hundred drugs of our modern pharmacopeia are efficacious and useable as antibiotics (ATBs) in medicine; they are used to kill or block growth of bacteria. Bactericidal ATBs can induce a common oxidative damage pathway, leading to the production of reactive oxygen species and cell death. ATBs can also damage various mammalian cell types and tissues but mechanisms of action remain relatively unclear. Both bactericidal and bacteriostatic ATBs can target mitochondria but only the former usually induce mitochondrial dysfunction and oxidative stress at clinically relevant doses. Human liver is a major target of ATBs of which toxicity is mostly idiosyncratic. Interestingly, β-lactam penicillinase-resistant ATBs, which are known to cause mostly immune reactions in patients, induce an early endoplasmic reticulum stress in in vitro human hepatocytes at low concentrations; this stress is inhibited by activation of the HSP27 protein which acts as a protective response associated with occurrence of cholestatic features. In this review, we analyze the importance of oxidative and endoplasmic reticulum stress in cellular damage induced by ATBs, especially in hepatocytes and highlight specific cellular protection mechanisms associated with penicillinase-resistant ATB treatments.