Dental plaque is closely related to the occurrence of dental caries, of which the main causative bacterium is Streptococcus mutans (S. mutans). In this study, to create potent antibiofilm agents, we chose a human antimicrobial peptide LL-37 as our starting material and modified it by cutting it shorter and varying its charge and hydrophobicity. The results of anti-S. mutans as well as biofilm inhibitory activity tests indicated that two derivatives, IG-13-1 and IG-13-2, were the most potent one toward both planktonic and biofilm S. mutans cells with the minimal inhibitory concentration of 5.0 μM and minimal biofilm inhibitory concentrations of 5.91 ± 0.91 μM and 7.58 ± 0.23 μM, respectively. The modes of action study showed that IG-13-1 and IG-13-2 were functioned by disrupting the bacterial membrane, causing the leakage of inner contents, thereby leading to the death of bacterial cells eventually. In addition, IG-13-1 and IG-13-2 were able to suppress the expression of proinflammatory cytokine of TNF-α and reduce the level of nuclear transcription factor-κB, which indicated the potential anti-inflammatory activity of these peptides. Conclusively, this study indicated that IG-13-1 and IG-13-2 are potent peptides in both anti-S. mutans and anti-inflammatory activities, therefore, showing a potential application for the prevention and treatment of dental caries.