(1) Background: Various materials are available for CAD-CAM denture base fabrication, for both additive and subtractive manufacturing. However, little has been reported on bond strength to soft denture liners. Therefore, the aim of this study was to investigate tensile bond strength, comparing between different denture base materials and soft denture liners. (2) Methods: Seven different materials were used for denture base fabrication: one heat-polymerized polymethyl methacrylate, three materials for subtractive manufacturing, two materials for additive manufacturing and one polyamide. Two materials were used for soft denture lining: one silicone-based and one acrylate-based. The study was conducted according to the specification ISO No. 10139-2:2016, and the type of failure was determined. The Kruskal–Wallis test with Dunn’s post hoc test was used to analyse the values of tensile bond strength, and Fisher’s exact test was used to analyse the type of failure.pValues < 0.05 were considered statistically significant. (3) Results: The tensile bond strength values were not statistically significantly different combining all the materials used for denture base fabrication with the acrylate-based soft denture liner (p> 0.05), and the average values ranged between 0.19 and 0.25 Mpa. The tensile bond strength values of the different denture base materials and silicone-based denture liner were statistically significantly different (p< 0.05), and the average values ranged between 1.49 and 3.07 Mpa. The type of failure was predominantly adhesive between polyamide and both additive-manufactured denture base materials in combination with the acrylate-based soft liner (p< 0.05). (4) Conclusions: The use of digital technologies in denture base fabrication can have an influence on different tensile bond strength values for soft denture liners, with different types of failure when compared with heat-cured PMMA. Similar tensile bond strength values were found between the acrylate-based soft denture liner and denture base materials. Significant differences in tensile bond strength values were found between the silicone-based soft denture liner and denture base materials, where the additive-manufactured and polyamide denture base materials showed lower values than heat-cured PMMA and subtractive-manufactured denture base materials.