Plant seed oil is often incorporated into the cream emulsions to provide multifunctional effects on the skin. In the current study, pumpkin seed oil (PSO) was used to develop a stable oil-in-water emulsion. The study aimed to optimise PSO cream formulation and determine the synergistic effect of the PSO with vitamin E oil added. The physical properties, antioxidant activities and storage stability of the formulations were analysed. Besides, the synergistic effect of the best formulation was analysed based on α-tocopherol content using ultra-high performance liquid chromatography (UHPLC). The storage stability test was assessed upon storing at 25 ± 2°C and 40 ± 2°C for 12 weeks. The best formulation (20% PSO, vitamin E oil and beeswax) selected showed physically and microbiologically stable. The incorporation of vitamin E oil into the formulation produced with PSO was found to be compatible, as it showed a synergistic effect in the amount of α-tocopherol content (combination index (CI) = 0.98). Thus, PSO had shown its potency to be incorporated into the topical products with a promising potential in delivering additional properties that can nourish the skin.