Osteomyelitis is an inflammation of the bone caused by bacterial infection. It usually develops from broken bones, decayed teeth, or heavily punctured wounds. Multi-drug-resistant bacteria are the major hurdle in the treatment of osteomyelitis. The ever-rising antibiotic resistance even leads to amputations or fatalities as a consequence of chronic osteomyelitis. Hence, a single agent with antibacterial activity as well as bone regenerative properties can serve as a potential off-the-shelf product in the treatment of osteomyelitis. Herein, the antibacterial and pro-osteogenic characteristics of copper sericin (Cu-SER) metal–organic frameworks (MOFs) are reported. Sericin, a silk protein with antibacterial activity and an osteoinduction property, acts as an organic template for the deposition of Cu-SER MOFs, similar to collagen during biomineralization in bone. The MOFs exhibit cytocompatibility and osteogenic activity in a dose-dependent manner, as revealed by cell proliferation (alamarBlue) and mineralization (Alizarin Red S and Energy Dispersive X-Ray analysis). The bactericidal activity of Cu-SER MOFs was investigated by scanning electron microscopy and a growth kinetic analysis. Together, the report illuminates the unique phenomenon of Cu-SER MOFs that kill bacteria upon contact while being well-tolerated by primary human cells. Hence, Cu-SER MOFs hold the potential to minimize antibiotic dependence.