Highly contagious avian influenza virus' (AIV) subtypes, including H5N1 and H5N8 are considered as serious threats for poultry industry. Despite its severity, treatment and mitigation attempts are fall into baffling. Though a few approved anti-influenza medications are available, the M2 channel blockers amantadine and rimantadine, as well as the neuraminidase inhibitor oseltamivir are being less effective due to widespread drug resistance. To cope up with these circumstances, scientists have found nucleoprotein as a novice drug targeting site for H5N1. Hence, the current study used a rational screening method to find the best candidates for nucleoprotein inhibitors of H5N1 subtype and neuraminidase inhibitors for H5N8 subtype against pathogenic AIV. Finding the best candidates, molecular docking method and computational pharmacokinetics and pharmacology was developed to estimate the potential of the multi-targeting fungal-derived natural compounds for the development of drug. Chevalone E compound was found as the best inhibitor for both nucleoprotein and neuraminidase of H5N1 and H5N8 subtypes respectively, whereas, Brevione F and Brocazine-A for nucleoprotein with Penilactone-A and Aspergifuranone for neuraminidase. In case of drug prediction, the study recommends Estramustine and Iloprost against both nucleoprotein and neuraminidase. Besides these, Butorphanol, Desvenlafaxine, Zidovudine and Nadolol are the best drug candidates for nucleoprotein inhibitors, meanwhile, Sitaxentan, Ergoloid mesylate, Capecitabine and Fenoterol act as speculated candidates against neuraminidase.