Nucleosides have been extensively studied since the discovery of the structure and role of nucleic acids in biological processes. Several approaches have been developed to synthesize nucleosides and nucleoside analogues and, amongst them, the Sonogashira cross-coupling strategy has been a widely employed methodology. Hence, this review provides an overview of the synthesis of nucleosides and their analogues by the Sonogashira cross-coupling approach over the last three decades. Furthermore, the therapeutic relevance of the synthesized compounds will also be highlighted.