Objectives: To synthesize and evaluate the physicochemical, antimicrobial, and cytocompatibility properties of experimental resin-based endodontic sealers containing butia or copaiba natural oils. Methods: Experimental groups contained butia (Butia capitata) at 0.5 % (B0.5), 1 % (B1), 2 % (B2), and copaiba (Copaifera spp.) at 0.5 % (C0.5), 1 % (C1), and 2 % (C2). The control group contained no added oils (experimental material, EM) and the commercial group was a methacrylate-based resin material (RealSeal™, SybronEndo Corporation, Orange, CA, USA). Degree of conversion, film thickness, setting time, flow, water sorption and solubility, and radiopacity were measured. Meanwhile, antimicrobial (modified direct contact test) and cytotoxicity assays of the experimental groups and controls were performed. One-way ANOVA was used to determine the effect of the independent variable (material) on the degree of conversion, film thickness, radiopacity, flow, setting time, water sorption and solubility, and cytotoxicity. For antimicrobial assays, data were analyzed using two-way ANOVA and Ŝidák's test. Results: The experimental groups containing natural oils showed higher values of degree of conversion, and lowest water sorption and solubility. EM, B0.5, B1, B2, and RS showed similar film thicknesses. The flow values were statistically similar in all groups. The experimental groups showed adequate cell compatibility. Copaiba oil at 2% increased the antimicrobial effect after 1 and 24 h (p < 0.05). The incorporation of butia or copaiba resulted in a slight modification in some physicochemical properties of the experimental resin sealers. Conclusion: Novel resin sealers containing natural oils are a promising alternative for endodontics, because of their good physicochemical properties, antimicrobial effects, and cytocompatibility when compared to a commercially available sealer. Clinical significance: Endodontic sealers containing butia or copaiba had satisfactory cytocompatibility, antimicrobial effects, and adequate physicochemical properties.