Optimal vision remains one of the most essential elements of the sensory system continuously threatened by many ocular pathologies. Various pharmacological agents possess the potential to effectively treat these ophthalmic conditions; however, the use and efficacy of conventional ophthalmic formulations is hindered by ocular anatomical barriers. Recent novel designs of ophthalmic drug delivery systems (DDS) using nanotechnology show promising prospects, and ophthalmic formulations based on nanotechnology are currently being investigated due to their potential to bypass these barriers to ensure successful ocular drug delivery. More recently, stimuli-responsive nano drug carriers have gained more attention based on their great potential to effectively treat and alleviate many ocular diseases. The attraction is based on their biocompatibility and biodegradability, unique secondary conformations, varying functionalities, and, especially, the stimuli-enhanced therapeutic efficacy and reduced side effects. This review introduces the design and fabrication of stimuli-responsive nano drug carriers, including those that are responsive to endogenous stimuli, viz., pH, reduction, reactive oxygen species, adenosine triphosphate, and enzymes or exogenous stimuli such as light, magnetic field or temperature, which are biologically related or applicable in clinical settings. Furthermore, the paper discusses the applications and prospects of these stimuli-responsive nano drug carriers that are capable of overcoming the biological barriers of ocular disease alleviation and/or treatment for in vivo administration. There remains a great need to accelerate the development of stimuli-responsive nano drug carriers for clinical transition and applications in the treatment of ocular diseases and possible extrapolation to other topical applications such as ungual or otic drug delivery.