The resolution of the multifarious challenges faced by countries of the Global South has evoked active debate and concern by experts and senior political and multilateral representatives all over the world for the last many decades. A plethora of studies, research and analyses on this theme have already been undertaken, and a review in this regard is ongoing. Given the complexity and extent of the challenges and the bearing that these issues have on the prosperity and well-being of millions in our world, it would be presumptuous to suggest that any single solution or panacea can be effective in this regard. Based on this premise, this paper constitutes yet another attempt to understand the rigours of this issue in light of contemporary economic and political developments. The absence of adequate and optimal allocation of economic resources for addressing the predicament of the Global South has always been a major constraint. Some authors have likened these symptoms to neo-colonialism. COVID-19 has seriously aggravated the severity of such bottlenecks. As the availability of data about the subject continues to be constrained by data-collection capabilities and facilities in the South, this paper relies on a review of diverse academic, multilateral and other commentaries, literature, and documents to simulate overview perspectives in this regard. A key finding that emerges from an analysis of the above is that if problems associated with the mounting economic divide and state of prolonged economic neglect and deprivation in many countries of the South continue unchecked, repudiation and rejection of ongoing economic and political processes in the contemporary World Order cannot be entirely ruled out. In the social media-based and online-connected world today, such rejection could rapidly deteriorate into major social unrest and disturbances that might be even more vigorous and pronounced than those witnessed during the Arab Spring. In such exigencies, the prosperity and fortunes of business entities in the North, which heavily rely on the purchasing power of the populated Global South, will stand compromised. Such trends could also pose existential threats. A reformatting of paradigms, both in the North and in the South, is, therefore, both necessary and inevitable. Some of the perspectives that could be urgently considered in this regard—which by no means are the only ones—are what this paper seeks to draw attention to.