In recent years, minimally invasive drug delivery systems (MIDDS) have gained enormous attention of the researchers as they provide creative ways to achieve accurate and effective therapeutic effects while reducing procedural risks and patient pain. The concepts of MIDDS were used in the treatment of various diseases such as cardiovascular diseases, central nervous system-related disorders, respiratory diseases, cancer, and diabetes. The delivery of therapeutic agents in all the above cases utilizes invasive procedures. So, there is a need in developing the potential systems that bypass all types of limitations of traditional oral or intravenous routes and improve both patient compliance and bioavailability of therapeutic agent. The system that has all the required qualities includes transdermal, nose to brain, inhalational, and nanomedicines. The present chapter begins by specifying the primary mechanisms of key MIDDS such as intranasal, hydrogel, nanoparticles, nose to brain, and transdermal systems. Further the chapter also explores the inclusion of nanotechnology that allows for controlled and targeted drug delivery. The clinical effectiveness and safety profiles of the system were highlighted by some case studies related to cancer, diabetes, pain control, CNS disorders, and cardiovascular disorders. MIDDS play a critical role in tackling issues related to chronic diseases by providing solutions that lessen systemic adverse effects and enhance treatment outcomes. Lastly, to satisfy the changing demands of patients and healthcare systems throughout the world, this chapter highlights the revolutionary potential of MIDDS in transforming healthcare delivery, with an emphasis on overcoming present constraints and encouraging innovation.