Rabies, a viral illness classified as a neglected tropical disease by the World Health Organization (WHO), causes thousands of people to die annually, primarily in underprivileged communities of Africa and Asia. In the context of a single health framework, one of the primary objectives of this literature review is to examine the major factors and challenges that maintain the endemic status of dog-mediated human rabies in Pakistan. Rabies-endemic countries have an imperative need to work on preventive strategies to lessen the burden of this terrible disease as per guidelines of World Organization for Animal Health (WOAH) and WHO. Lack of public awareness, free-roaming dogs, and cold chain mismanagement of vaccinations are the 3 most significant factors contributing to the increasing number of dog bite injuries and suspected rabies cases in animals and humans. To control dog-mediated rabies, Pakistan must initiate and strongly support a national One Health project, a subsidized supply of human and animal rabies vaccine in public hospitals, and designated rabies prevention centers at an affordable cost. People should be educated regarding responsible pet ownership and follow-up of basic preventive measures. Empowerment of labs equipped with surveillance systems are also additionally required to strengthen rabies control and prevention activities at least in regional levels. This article gives valuable information for scholars and policymakers who wish to comprehend why this disease remains endemic due to multiplex interplay of zoonotic, medical, and anthropological risk factors and transmission chains in animal and human sectors through viral reservoirs. Achieving the 'Zero By 2030' goal in Pakistan requires joint immediate action from the government, society, and all health departments at regional, provincial, and national level..