This study incorporated the concept of mini-bioreactors by employing additive manufacturing procedures. Limitations in experimental studies with large-scale equipment favor the use of mini-reactor systems and help to understand the phenomena of its large-scale counterpart better. 3D printing enables to reproduce the reaction engineering principles in a low-cost and ease of manufacture way and expedites the development of novel prototypes. Small anaerobic digesters of 40 mL were designed and fabricated to investigate the effect of downscaling on the stability and performance of the anaerobic digestion process. Baseline tests were conducted using a commercial 400-mL stirred bioreactor as reference for further comparison and validation. Miniature bioreactors showed similar stability and conversion efficiency. However, the biogas production rate and methane content of the 3D-printed bioreactors were lower than those in the baseline study bioreactors. Finally, 3D-printed systems were linked with efficient performances and are considered as an excellent opportunity for analyzing microbe-mediated bioenergy systems. This study demonstrated the high potential of miniaturized bioreactors as a process screening tool.