Antibiotics are considered as a cornerstone of modern medicine and their discovery offers the resolution to the infectious diseases problem. However, the excessive use of antibiotics worldwide has generated a critical public health issue and the bacterial resistance correlated with antibiotics inefficiency is still unsolved. Finding novel therapeutic approaches to overcome bacterial resistance is imperative, and natural compounds with antibacterial effects could be considered a promising option. The role played by antibiotics in tumorigenesis and their interrelation with the microbiota are still debatable and are far from being elucidated. Thus, the present manuscript offers a global perspective on antibiotics in terms of evolution from a historical perspective with an emphasis on the main classes of antibiotics and their adverse effects. It also highlights the connection between antibiotics and microbiota, focusing on the dual role played by antibiotics in tumorigenesis. In addition, using the natural compounds with antibacterial properties as potential alternatives for the classical antibiotic therapy is discussed.