Introduction: Antibiotic resistance is a growing concern in health care. Methicillin-resistant Staphylococcus aureus (MRSA), forming biofilms, is a common cause of resistant orthopedic implant infections. Gentamicin is a crucial antibiotic preventing orthopedic infections. Silica–gentamicin (SiO 2 -G) delivery systems have attracted significant interest in preventing the formation of biofilms. However, compelling scientific evidence addressing their efficacy against planktonic MRSA and MRSA biofilms is still lacking, and their safety has not extensively been studied. Materials and methods: In this work, we have investigated the effects of SiO 2 -G nanohybrids against planktonic MRSA as well as MRSA and Escherichia coli biofilms and then evaluated their toxicity in zebrafish embryos, which are an excellent model for assessing the toxicity of nanotherapeutics. Results: SiO 2 -G nanohybrids inhibited the growth and killed planktonic MRSA at a minimum concentration of 500 µg/mL. SiO 2 -G nanohybrids entirely eradicated E. coli cells in biofilms at a minimum concentration of 250 µg/mL and utterly deformed their ultrastructure through the deterioration of bacterial shapes and wrinkling of their cell walls. Zebrafish embryos exposed to SiO 2 -G nanohybrids (500 and 1,000 µg/mL) showed a nonsignificant increase in mortality rates, 13.4±9.4 and 15%±7.1%, respectively, mainly detected 24 hours post fertilization (hpf). Frequencies of malformations were significantly different from the control group only 24 hpf at the higher exposure concentration. Conclusion: Collectively, this work provides the first comprehensive in vivo assessment of SiO 2 -G nanohybrids as a biocompatible drug delivery system and describes the efficacy of SiO 2 -G nanohybrids in combating planktonic MRSA cells and eradicating E. coli biofilms.