According to the Global Antimicrobial Resistance and Use Surveillance System (GLASS) data, antibiotic resistance escalates more challenges in treatment against communicable diseases worldwide. Henceforth, the use of combinational antimicrobial therapy and metal-conjugated phytoconstituents composites are considered as alternatives. The present study explored the efficacy of mercuric-sulfide-based metallopharmaceutical, Sivanar Amirtham for anti-bacterial, anti-tuberculosis, anti-HIV therapeutics and toxicity profile by haemolytic assay, first of its kind. The anti-bacterial study was performed against both gram-positive and gram-negative pathogens including Staphylococcus aureus (ATCC 29213), Methicillin-resistant Staphylococcus aureus (MRSA: ATCC 43300), Enterococcus faecalis (ATCC 29212), Pseudomonas aeruginosa (PA14) and Vibrio cholerae (MTCC 3905) by agar well diffusion assay, wherein the highest zone of inhibition was identified for MRSA (20.7 mm) and V. cholerae (34.3 mm) at 25 mg/mL. Furthermore, the anti-tuberculosis activity experimented by microtitre alamar blue assay against M. tuberculosis (ATCC 27294) demonstrated significant activity at the concentration range of 12.5–100 µg/mL. Additionally, the anti-HIV efficacy established by the syncytia inhibition method using C8166 cell lines infected with HIV-1IIIB, showed a significant therapeutic effect. The in-vitro toxicity assay proved Sivanar Amirtham to be non-haemolytic and haemocompatible. The physicochemical characterization studies revealed the nano-sized particles with different functional groups and the distinctive metal–mineral complex could be attributed to the multi-site targeting ability. The rationale evidence and scientific validation for the efficacy of Sivanar Amirtham ensures that it could be proposed as an alternative or adjuvant for both prophylactics and therapeutics to overcome HIV infection and antimicrobial resistance as well as the multi-drug resistance challenges.