Aim: The aim of the present study was to evaluate the wettability of three saliva substitutes on heat-polymerized acrylic resin. Materials and methods: Heat-cured acrylic resins 150 were made and divided into three groups containing 50 samples each, i.e., group 1 Aqwet, group 2 Biotene, and group 3 Mouthkote. The prepared wax pattern was cut using 30 × 30-mm two square glass plates along the sides using a sharp carver. The uniformity of the wax samples was checked using the wax gauge. The wax samples were invested using dental plaster in varsity flasks. The samples were prepared using conventional heat-cure denture base acrylic resin. A goniometer was used to calculate receding and advancing contact angles for dynamic contact angle analysis. Results: The least mean value of advancing and receding contact angles was seen in group 1 Aqwet (68.12 ± 1.30 and 58.56 ± 0.10) followed by group 2 Biotene (81.64 ± 0.88 and 74.89 ± 0.45), and group 3 Mouthkote (85.76 ± 1.02 and 80.63 ± 0.66). A significant difference was found between the groups statistically with a p value of 0.001. A significant difference was found on multiple comparisons between group 1 vs group 3 and group 1 vs group 2 with different receding and advancing contact angles of saliva substitutes analyzed with Turkey's post hoc test. Conclusion: The lowest advancing and receding contact angle values were significantly seen in the Aqwet saliva substitute followed by Biotene and Mouthkote on heat-polymerized acrylic resin. Clinical significance: The clinical significance of the saliva substitute's good wetting property on acrylic denture base. The quality of life of the patients with xerostomia can be improved using a suitable saliva substitute.