Microneedles are one of the most prominent approaches capable of physically disrupting the stratum corneum without devastating the deeper tissues to deliver both small molecules and macromolecules into the viable epidermis/dermis for local/systemic effects. Over the past two decades, microneedles have caught the attention of many researchers because of their outstanding advantages over oral and parenteral drug delivery systems such as self-administration, pain-free, steady-plasma concentration maintenance, avoidance of first-pass hepatic biotransformation, and so on. So far, scientists have reported various types of microneedle patches to deliver the loaded therapeutics as soon as the microneedles are inserted into the skin, regardless of the demand for therapeutics to treat a specific condition. This way of drug delivery can lead to potential risks such as poor therapeutic efficacy or drug overdose. The stimuli-responsive microneedles are the most predominant tool to achieve the on-demand/need-based drug delivery, leading to safe and effective treatment. Various natural and synthetic polymers that can undergo significant transitions such as swelling, shrinking, dissolution, or disintegration play a pivotal role in the development of stimuli-responsive microneedles. The current Review provides brief information about the history, emergence, type, and working principles of microneedles. Furthermore, it selectively discusses various exogenous and endogenous stimuli-responsive microneedles along with their mechanism of action involved in treating different disease conditions. Collaterally, the emergence of "closed-loop" combinatorial stimuli-responsive microneedle patches for precise delivery of therapeutics is meticulously canvassed. Subsequently, it covers the patents of different stimuli-responsive microneedles and further highlights the existing challenges and future perspectives concerning clinical application and large-scale production.