Monkeypox (MPOX) is a zoonotic disease with roots tracing back to Western and Central Africa since its initial appearance in humans in 1970. However, the recent upsurge in MPXV outbreaks spanning over 100 nations has sparked substantial concern. In the present investigation, we examine the relative abundance (RA) and relative density (RD) of simple sequence repeats (SSRs) among the global collection of 404 MPOX genomes. Our analysis brings to light substantial shifts in the RA and RD of SSRs as they show transition across temporal spans, from ancient to contemporary lineages. The majority of SSR variations were found in Clades I, IIa, and IIb. Notably, each of the three clades exhibits distinct SSR motifs that are unique to their respective clades. Furthermore, our exploration identifies 26 conserved SSR regions exclusive to MPXV that could be used as molecular or diagnostic markers, and hold potential for vaccine development as well. Moreover, 10 variable SSR hotspot sites were discovered in nine genes with the highest variation in the MPXV genome. Notably, these nine genes have been found to be involved in surface protein synthesis and host regulation, which may have implications for monkeypox pathogenesis and evolution.