Molecules derived from natural products (NPs) have many applications in health and disease; due to their versatility, safety, and cost-effectiveness. This study compared the anti-inflammatory properties of a topical cream made using Ocimum gratissimum extract both alone and in combination with Cucurbita ‘pumpkin’ seed oil (PSO) with a commercially available product. Wistar rats, comprising males and non-pregnant females weighing between 250 and 300 g, were divided into four groups (A to D), with 3 rats in each group. They received four different cream batches, 1 to 4, respectively (after sub-acute inflammation was induced). The creams from batches ‘1’ and ‘2’ contained NPs, while batches ‘3’ and ‘4’ contained excipients devoid of NPs and the commercial product, respectively. Batch ‘1’ contained O. gratissimum and PSO, but batch ‘2’ contained only O. gratissimum. The extract obtained from O. gratissimum was also subjected to gas chromatograph flame ionization detector (GC-FID) analysis. The result after the treatments showed that the cream from batch ‘1’ achieved 100% inflammation inhibition on the fourth day, while the commercial product ‘batch 4’ achieved the same feat on the eighth day of application. The GC-FID analysis revealed components with recognized anti-inflammatory properties, such as quercetin, naringenin, steroids, etc.; and the physical stability parameters for the cream batches didn’t significantly change during an assessment period of sixty days. Conclusively; topical creams formulated with O. gratissimum and PSO are effective for skin inflammations, are stable, and outperformed the commercially available products to which they were compared.