<p>Acne vulgaris is an immune-mediated inflammatory skin condition. It is the 8th most treated skin condition, affecting over 80% of teenagers globally. The pathophysiology of the disease is intricate and involves the interaction of multiple factors, including hyperactivation of sebaceous glands, abnormal hyperkeratinization of pilosebaceous follicles, dysbiosis of microflora, and, subsequently, immune-mediated inflammation. Due to the multifaceted nature of the disorder, a combination of different anti-acne agents is preferred. However, synthetic topical anti-acne agents such as retinol derivatives and benzoyl peroxide are often associated with common side effects such as redness, dryness, peeling, irritation, and eczema. Also, increasing cases of multidrug resistance against commonly used antibiotics further reduce the therapeutic effectiveness of the treatment and upsurge the overall expense. Many studies validate using plant extracts and secondary metabolites for treating acne. Alongside synergistic formulations, the co-delivery of synthetic and herbal agents is emerging as the latest target for developing novel and efficient acne treatments. This article summarizes the comprehensive pathophysiology of the disease, classification, and grading system evolution, along with detailed information on different FDA-approved synthetic topical and systemic anti-acne agents (retinoids, antibiotics, and diverse medications). In addition, we highlight the new investigation on several phytoconstituents and secondary metabolites for treating acne vulgaris. Finally, we have attached the details of all the ongoing clinical trials on acne therapy.</p>