<p>Vitamin B₁₂ is a vital nutrient for the normal functioning of many metabolic processes. It has a characteristic corrinoid ring structure with a cobalt ion. Its complex chemical structure demands 30 enzyme-catalyzed steps for synthesis. Deficiency of this vitamin is common among individuals who are predominantly on a strict vegetarian diet. Large-scale production of this vitamin for dietary supplementation is primarily through microbial fermentation. This review discusses various computational approaches to improve vitamin B₁₂ biosynthesis in microbes, namely metabolic engineering, synthetic biology, comparative genomics and molecular docking. Recent advancements, such as CRISPR-Cas9-based genome editing, artificial intelligence-driven pathway optimization, and the integration of multi-omics data, have revolutionized microbial engineering for enhanced cobalamin production. How these strategies maximize cobalamin biosynthesis in response to the increasing demand for this essential nutrient is discussed in this review. Using relevant case studies and references, the evaluation explores the unique advantages, disadvantages, features, and initiatives of each approach. The conclusion emphasizes the central role of these methods in advancing the field of microbial biotechnology addressing industrial challenges, and generating new ideas to improve vitamin B₁₂ biosynthesis for global nutritional and therapeutic applications.</p> Graphical Abstract <p></p>