The discovery of antibiotics was one of the greatest achievements in human history, however, antibiotic resistance evolved no later than the introduction of antibiotics. The rapid evolution of antibiotic-resistant pathogens soon became frightening and remained a global healthcare threat. There is an urgent need to have new alternatives or new strategies to combat the multi-drug resistant superbugs such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), carbapenem-resistant Pseudomonas aeruginosa (CR-PA), extended-spectrum β-lactamases (ESBL) bearing multidrug-resistant Acinetobacter baumannii (MDR-AB), Escherichia coli (E. coli), and Klebsiella pneumoniae (K. pneumoniae). Antimicrobial peptides (AMPs) have been considered promising agents equipped with unique mechanisms of action along with several other benefits to fight the battle against drug-resistant superbugs. Overall, the current review summarizes the mechanisms of drug-resistant development, the mechanism of action adopted by AMPs to combat drug-resistant pathogens, and the immunomodulatory properties of AMPs. Additionally, we have also reviewed the synergistic potential of AMPs with conventional antibiotics along with the associated challenges and limitations of AMPs in the way of pharmacological development for therapeutic applications in clinical settings.