Background Messenger RNA (mRNA) vaccines emerged as a powerful tool in the fight against infections. Unlike traditional vaccines, this unique type of vaccine elicits robust and persistent innate and humoral immune response with a unique host cell‐mediated pathogen gene expression and antigen presentation. Methods This offers a novel approach to combat poxviridae infections. From the genome of vaccinia and Mpox viruses, three key genes (E8L, E7R, and H3L) responsible for virus attachment and virulence were selected and employed for designing the candidate mRNA vaccine against vaccinia and Mpox viral infection. Various bioinformatics tools were employed to generate (B cell, CTL, and HTL) epitopes, of which 28 antigenic and immunogenic epitopes were selected and are linked to form the mRNA vaccine construct. Additional components, including a 5′ cap, 5′ UTR, adjuvant, 3′ UTR, and poly(A) tail, were incorporated to enhance stability and effectiveness. Safety measures such as testing for human homology and in silico immune simulations were implemented to avoid autoimmunity and to mimics the immune response of human host to the designed mRNA vaccine, respectively. The mRNA vaccine's binding affinity was evaluated by docking it with TLR‐2, TLR‐3, TLR‐4, and TLR‐9 receptors which are subsequently followed by molecular dynamics simulations for the highest binding one to predict the stability of the binding complex. Results With a 73% population coverage, the mRNA vaccine looks promising, boasting a molecular weight of 198 kDa and a molecular formula of C8901H13609N2431O2611S48 and it is said to be antigenic, nontoxic and nonallergic, making it safe and effective in preventing infections with Mpox and vaccinia viruses, in comparison with other insilico‐designed vaccine for vaccinia and Mpox viruses. Conclusions However, further validation through in vivo and in vitro techniques is underway to fully assess its potential. The article presents the development of a novel messenger RNA (mRNA) vaccine targeting poxviridae infections. Through bioinformatics analysis and molecular simulations, the vaccine construct containing 28 antigenic epitopes was designed, with safety measures to avoid autoimmunity. The mRNA vaccine demonstrated promise, showing potential for preventing infections with Mpox and vaccinia viruses.