<p>Topical semisolid formulations such as creams, ointments, and gels play a critical role in dermatological therapy by delivering drugs locally while minimizing systemic exposure. However, their complex microstructures and sensitivity to formulation and process variables pose significant risks to bioequivalence. Quality by Design (QbD), as outlined in ICH guidelines, provides a systematic framework for integrating product and process understanding into development through risk assessment, design of experiments (DoE), and control strategies. This systematic review aimed to critically evaluate the application of QbD principles in the development of topical semisolid formulations, focusing on the identification of Critical Quality Attributes (CQAs), the role of DoE in optimization, and the implementation of control strategies to ensure robust quality, scalability, and regulatory compliance. Following PRISMA 2020 guidelines, a systematic search was conducted in PubMed and Google Scholar (June–August 2025) using predefined Boolean queries. Studies were included if they reported on the application of QbD to topical semisolids with detailed descriptions of CQAs, DoE, and control strategies. A total of 85 articles meeting the eligibility criteria were extracted, evaluated for methodological quality of included articles, and synthesized narratively across thematic categories. Two independent reviewers performed data extraction, with discrepancies resolved through discussion, and findings were synthesized narratively. Out of 5,692 records identified, 85 studies were included from Google Scholar and PubMed: 46 employed factorial/DoE methodologies, 26 investigated bioequivalence and in vitro release/permeation, and 12 involved clinical or pharmacokinetic studies. Evidence demonstrated that QbD enhances formulation robustness and reproducibility by systematically identifying CQAs such as viscosity, particle size, stability, and drug release. DoE approaches, including factorial, central composite, and mixture designs, were shown to optimize formulation and process parameters efficiently while enabling scalability. Control strategies integrating risk management and analytical QbD provided enhanced product understanding but remain underutilized, with gaps in harmonized regulatory standards, microstructural equivalence (Q3), and predictive bioequivalence (Q4) assessments. Overall, the QbD principles significantly improve the development of topical semisolid formulations by ensuring systematic control of formulation and process variability, thereby enhancing product quality, consistency, and regulatory alignment.</p><p>Persistent challenges remain in achieving microstructural and performance equivalence, scalability, and harmonized global regulatory acceptance. Future directions should emphasize the integration of advanced tools such as process analytical technology (PAT) and patient-centric quality attributes to strengthen clinical relevance and enable reliable therapeutic equivalence.</p>