Bioprocess development for umqombothi (a South African traditional beer) as with other traditional beer products can be complex. As a result, beverage bioprocess development is shifting towards new systematic protocols of experimentation. Traditional optimization methods such as response surface methodology (RSM) require further comparison with a relevant machine learning system. Artificial neural network (ANN) is an effective non-linear multivariate tool in bioprocessing, with enormous generalization, prediction, and validation capabilities. ANN bioprocess development and optimization of umqombothi were done using RSM and ANN. The optimum condition values were 1.1 h, 29.3 °C, and 25.9 h for cooking time, fermentation temperature, and fermentation time, respectively. RSM was an effective tool for the optimization of umqombothi’s bioprocessing parameters shown by the coefficient of determination (R2) closer to 1. RSM significant parameters: alcohol content, total soluble solids (TSS), and pH had R2 values of 0.94, 0.93, and 0.99 respectively while the constructed ANN significant parameters: alcohol content, TSS, and viscosity had R2 values of 0.96, 0.96, and 0.92 respectively. The correlation between experimental and predicted values suggested that both RSM and ANN were suitable bioprocess development and optimization tools.