The present study aimed to diagnose infectious myonecrosis virus (IMNV) and infectious hypodermal and hematopoietic necrosis virus (IHHNV) among cultured penaeid shrimp (Penaeus semisulcatus, n = 120) collected from private farms in 2 Egyptian provinces (Damietta and North Sinai) along the Mediterranean coast. The collected shrimp were subjected to clinical examination, histopathology, molecular characterization, and phylogenetic analysis. Most of the shrimp infected with IMNV showed a distinctive appearance resembling cooked shrimp and white necrosis on distal abdominal segments and tail fans. Simultaneously, IHHNV-infected cases displayed opaque abdominal muscles, white milky to buff mottling on the shell, and a pathognomonic runt-deformity syndrome. Histopathological examination of infected specimens revealed muscular edema, hemocyte infiltration, deformities, Zenker’s necrosis, and eosinophilic intra-nuclear inclusion bodies (Cowdry type A). PCR results gave predictable amplicon sizes of 139 and 81 bp and confirmed the presence of IMNV and IHHNV with a total prevalence of 37.5 and 25%, respectively. A homology search by BLAST analysis showed that the retrieved isolates putatively belonged to IMNV and IHHNV based on 96.3 to 97% nucleotide identity to the corresponding open reading frame gene of each virus. The phylogenetic analysis clearly showed genetic similarity and cross-lineage between our isolates and other isolates from Egypt, the USA, Brazil, Indonesia, China, Korea, Taiwan, and Ecuador. In conclusion, gross inspection and histopathology may aid in the diagnosis of viral diseases; however, molecular tools are indispensable for confirming a possible infection. The current study recommends strict regulations during live shrimp transportation and implementing health control certificates over all imports and exports, especially in developing countries, including Egypt.