Hydrogel is one of the most prominent biomaterials in therapeutic and biomedical engineering, benefiting from its biocompatibility, chemical/physical tunability, and wide versatility to various fabrication techniques. One remarkable advance in the latest hydrogel research is the micro/nanofabrication technologies, which utilize unique mechanical and chemical properties of hydrogel, various chemical reaction mechanisms, and multidisciplinary approaches to realize innovative systems at these size scales. This review reports a comprehensive overview on the latest advances in fabrication of hydrogel-based micro- and nano-systems with an emphasis on their biomedical and therapeutic applications. Challenges and prospects are discussed from the material, fabrication, and system design perspectives to develop effective, personalized, and versatile hydrogel-based therapies.