Staphylococcus aureus is associated with serious invasive infections and high mortality rates due to a large number of toxins released. The persistent increasing resistance of S. aureus has driven the need for new anti-infection agents and innovative therapeutic strategies. RNAIII-inhibiting peptide (RIP) has been reported to reduce bacterial virulence by interfering with S. aureus quorum sensing system. The present study aimed to investigate whether two new RIP derivatives (RIP-V and RIP-L) could improve the survival rate of mice in a MRSA sepsis model. We found that neither anti-bacterial nor cell toxicity were displayed by all RIPs in vitro. In vivo protective effects were observed using a MRSA-induced mice sepsis model. Among RIPs, RIP-V exhibited the strongest protection function on mice survival and inhibition of pathological damages. Our studies firstly verified that RIPs could inhibited the RNAIII expression of S. aurues isolated from liver tissue of BALB/c mice. Moreover, RIP-V exhibited the strongest inhibitory effect on RNAIII and can decrease markedly the secretion of o-hemolysin in liver. These findings indicate that RIP-V might be considered as a potential and specific drug candidate for treating S. aureus infections, especially for MRSA.