Buruli ulcer caused by Mycobacterium ulcerans (M. ulcerans) is identified by a pain-free cyst or edema which develops into a massive skin ulcer if left untreated. There are reports of chemoresistance, toxicity, noncompliance, and poor efficacy of current therapeutic options. Previously, we used cheminformatics approaches to identify potential antimycobacterial compounds targeting major receptors in M. ulcerans. In this paper, we sought to identify potential bioactive compounds by targeting Cystathionine gamma-synthase (CGS) MetB, a key receptor involved in methionine synthesis. Inhibition of methionine synthesis restricts the growth of M. ulcerans. Two potent inhibitors Juglone (IC50 0.7 +/− 0.7 µmol/L) and 9-hydroxy-alpha-lapachone (IC50 0.9 +/− 0.1 µmol/L) were used to generate 3D chemical feature pharmacophore model via LigandScout with a score of 0.9719. The validated model was screened against a pre-filtered library of 2530 African natural products. Compounds with fit scores above 66.40 were docked against the structure of CGS to generate hits. Three compounds, namely Gentisic 5-O glucoside (an isolate of African tree Alchornea cordifolia), Isoscutellarein (an isolate of Theobroma plant) and ZINC05854400, were identified as potential bioactive molecules with high binding affinities of −7.1, −8.4 and −8.4 kcal/mol against CGS, respectively. Novel structural insight into the binding mechanisms was elucidated using LigPlot+ and molecular dynamics simulations. All three molecules were predicted to possess antibacterial, anti-ulcerative, and dermatological properties. These compounds have the propensity to disrupt the methionine synthesis mechanisms with the potential of stagnating the growth of M. ulcerans. As a result of reasonably good pharmacological profiling, the three drug-like compounds are potential novel scaffolds that can be optimized into antimycobacterial molecules.