Background: Myopathy is one of the most common adverse reactions of daptomycin and statins. We aimed to evaluate the muscular toxicity of the combination therapy of daptomycin and statins in a large pharmacovigilance database. Methods: This was a retrospective disproportionality analysis based on real-world data. All cases reported between the first quarter of 2004 and the fourth quarter of 2022 where daptomycin and statins were reported were gathered from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Disproportionality analyses were conducted by estimating the proportional reporting ratios (PRRs), reporting odds ratio (ROR), and information component (IC). Results: A total of 971,861 eligible cases were collected from the FAERS database. Data analysis showed that rosuvastatin (ROR: 124.39, 95% CI: 87.35–178.47), atorvastatin (ROR: 68.53, 95% CI: 51.93–90.43), and simvastatin (ROR: 94.83, 95% CI: 71.12–126.46) combined with daptomycin increased the reporting frequency of myopathy. Moreover, myopathy was reported more frequently with the 3-drug combination (ROR: 598.01, 95% CI: 231.81–1542.71). For rhabdomyolysis, the frequency of reports also increased when daptomycin was combined with rosuvastatin (ROR: 156.34, 95% CI: 96.21–254.05), simvastatin (ROR: 72.65, 95% CI: 47.36–111.44), and atorvastatin (ROR: 66.31, 95% CI: 44.06–99.81). Conclusions: The combination of daptomycin and statins increased the association of myopathy and rhabdomyolysis, especially with rosuvastatin, simvastatin, and atorvastatin.