The application of digitally manufactured dental metals has aroused the attention on their biocompatibilities. Three-dimensional oral mucosal model (3D OMM) would provide excellent assessments to the biocompatibility. In the current study, we set to measure metal ion release levels in the extracts of cast gold-platinum alloy (Au-Pt), differently manufactured cobalt-chromium alloy (Co-Cr) and commercially pure titanium (cp-Ti). We further tested two scaffold materials of 3D OMM to determine the better one for the succedent work. Lastly, we evaluated the apoptotic and autophagic effects of cast Au-Pt, and differently manufactured Co-Cr and cp-Ti on mucosal cells based on 3D OMM. We found that, in the construction of 3D OMM, Matrigel showed better performance than bovine acellular dermal matrix. Thus, Matrigel was chosen to construct the 3D OMM in the succedent studies. The results of ion release and biological assessments showed that, firstly, cast Au-Pt and cp-Ti triggered less early apoptotic cells and ion release than cast Co-Cr, implying better chemical stability and biocompatibility of them; secondly, digitally manufactured (including CAD/CAM milling and SLM) Co-Cr showed significantly lower ion release levels and lesser early apoptotic effects on 3D OMM as compared to the cast one. Although cast cp-Ti released much more ions than CAD/CAM milling one, manufacturing methods had no impact on apoptotic effect of cp-Ti. Therefore, we believe that digital methods possess same or even better chemical stability and biocompatibility than conventional casting one. Thirdly, although increased autophagic levels are observed in all test groups, so far there is no evidence that the test metals trigger different levels of autophagy as compared to each other. In addition, correlation analysis indicates that Co, W, and Mn appear to be the potential inducements for the apoptotic and autophagic effects of Co-Cr.