Background: Capsicum annuum L. and Capsicum frutescens L., of family Solanaceae, contain capsaicinoids with several pharmacological effects. However, their pungency limits the long-term use through the gastrointestinal tract. Objective: To obtain phytoformulations of microparticles containing capsaicinoids for reducing their pungency by oral route to achieve an anti-ulcer effect. Materials and Methods: Microparticles of poly(ε-caprolactone) containing capsaicinoids were prepared by simple emulsion/solvent evaporation. An optimized reverse-phase high-performance liquid chromatography method with ultraviolet (UV) detection for quantifying capsaicinoids into microparticle phytoformulations was then developed and validated. Chromatographic conditions consisted of a C18 reverse-phase analytical column (250 mm × 4.60 mm, 5 μm) using a mixture of acetonitrile and water (70:30 v/v) adjusted to pH 4.5 as mobile phase at a flow rate of 0.75 mL/min with UV detection at 280 nm. The developed method was validated as per the ICH guidelines with respect to specificity, linearity, limit of quantification, limit of detection, accuracy, precision, and robustness. The gastroprotective activity of pure capsaicinoids and loaded microparticles against ethanol-induced gastric ulcer in rats was performed. Results: Microparticles were successfully obtained. Analytical validation provided suitable results regarding all parameters investigated. These phytoformulations presented suitable encapsulation efficiency higher than 90%. Regarding the ulcerative lesion index (ULI) scores, poly(ε-caprolactone) (PCL) microparticles containing 5% of capsaicinoids (ULI = 16.3 ± 1.8 points) was statistically similar (P > 0.05) to ranitidine (ULI = 15.3 ± 1.4 points) and omeprazole (ULI = 8.0 ± 1.2 points). Conclusion: Capsaicinoids-loaded PCL microparticles reveal the potential to be suitable candidates as controlled drug delivery system for the therapeutic management of ulcer.