This study compares chemical and green synthesized zinc sulfide nanoparticles for multiple biological properties. A chemical synthesis approach is utilized to synthesize PEGylated ZnS‐NPs while the bulbs of Fritillariae cirrhosae bulbus are utilized for green synthesis. After extensive characterization, the NPs are examined for multifunctional biological properties such as antimicrobial, antioxidant, in vitro anticancer, and blood compatibility. Our study found that chemical synthesis results in higher yield and better dispersion behavior. However, the green ZnS‐NPs possessed increased antibacterial and antiparasitic potential against Leishmania tropica as the NPs resulted in significant inhibition against Staphylococcus aureus (S. aureus) and Bacillus subtilis (B. subtilis) with minimum inhibitory concentration (MIC) of 0.156 and 0.312 mg/mL, respectively while IC50 of 115.21 and 128.5 µg/mL were observed for the promastigote and amastigote forms of parasite. Furthermore, Fritillaria cirrhosa (F. cirrhosa) synthesized NPs possessed slightly improved antioxidant properties and in vitro anticancer potential against MCF‐7 breast cancer cells. Despite differences in the biological properties, the NPs did not result in hemolytic behavior thus demonstrating the compatible nature against blood cells. It was thus evident from the present study that the chemical and green synthesis techniques not only result in NPs with different physicochemical characteristics but also significantly influence the bio‐interaction of the obtained ZnS‐NPs.