Background: Hyperproliferative skin disorders (HSD) encompass a range of pathologies characterised by abnormal skin proliferation and differentiation. Cyclin-dependent kinases (CDKs) play a crucial role in regulating cell cycle progression. This study aimed to assess CDK5 and Ki-67 expression in psoriasis, verruca, and seborrheic keratosis, shedding light on their potential roles in the pathogenesis of hyperproliferative skin disorders. Methods: This case-control study included 80 participants, comprising patients with psoriasis, verruca, and seborrheic keratosis, as well as healthy controls. Dermoscopic, histopathological, and immunohistochemical evaluations of CDK5 and Ki-67 were conducted. Results: The study revealed a significant correlation between CDK5 expression and disease course in psoriasis, with progressive cases showing higher CDK5 levels. Additionally, a significant association was observed between CDK5 expression and the diffuse acanthosis pattern in psoriasis. In verruca, CDK5 expression was positively correlated with histopathological changes, particularly diffuse acanthosis and parakeratosis. CDK5 expression was highest in verruca compared to psoriasis, seborrheic keratosis, and controls. Conversely, Ki-67 expression was highest in psoriasis. Statistically significant differences were found in nuclear expression of both CDK5 and Ki-67 among the studied groups. Conclusions: CDK5 and Ki-67 may play distinct roles in the pathogenesis of hyperproliferative skin disorders. CDK5 appears to be more closely associated with verruca, while Ki-67 is highly expressed in psoriasis.