Osteosarcoma is a malignant condition affecting adolescents and children more than adults. Nanobiomedicine has opened up several avenues which have increased therapeutic efficiencies than the conventional treatment for the same. In the current study, a novel organic nanoparticle was devised conjugated with bisphosphonate zoledronic acid which has an affinity for bone tissues. Moreover, the nanoparticle was loaded with multiple anti-cancer drugs like gemcitabine and epirubicin. The nanoparticles were characterized by microscopic analysis, entrapment and loading efficiencies, bone affinity studies, in-vitro release studies, cytotoxicity studies and finally in-vivo tumor regression studies. Bone affinity studies depicted a high affinity of zoledronic acid towards bone powder. The nanoparticle exhibited a nanosize dimension, high entrapment and loading efficiencies with uniform symmetry devoid of agglomeration. The in-vitro release experiments showed a measured release of drugs over a longer time without any hint of burst release. However, the release was comparatively for a longer duration in acidic pH and normal physiological pH which may be excellent for therapeutic efficiency. The cytotoxicity studies revealed enhanced cytotoxic effect for MG-63 cell lines in comparison of free drug or single drug combinations. Nonetheless, they proved to be cytocompatible with primary bone cells. Additionally, cellular uptake of nanoparticle was appreciably improved. Significant tumor (250%) regression was seen upon treatment with multiple drug loaded zoledronic acid conjugated nanoparticle, along with epigenetic changes affecting microRNA expressions. The increased cytotoxicity and increased cellular uptake may be of greater advantage in systemic osteosarcoma therapy. Combining all results, our study demonstrated substantial potential towards management of osteosarcoma.