Recent advances in the synthesis of nanomaterials with diagnostic and therapeutic capabilities have been rapidly reshaping the landscape of precision medicine. Impressive progress has been made toward the design and production of innovative theranostic nanomaterials to treat a variety of diseases, yet their potential is currently limited by low bioavailability, biocompatibility, or undesirable pharmacokinetics, hindering their widespread clinical implementation. Here, we summarize the state of the art for theranostic nanoparticles and discuss the diverse administration routes being used in the diagnosis and treatment of different diseases. In addition to the most commonly used intravenous (IV) administration, newly emerging nanomaterial administration routes are described in depth to explore the potential benefits of these routes that can bypass biological barriers and thereby facilitate the delivery of nanoparticles to boost imaging sensitivity and therapeutic efficacy in specific use cases. Some of the biggest challenges facing nanoparticle delivery systems are site-specific targeting, controlled nanoparticle accumulation, and safe metabolic processing. By providing examples of their in vivo applications for various diseases, we highlight the benefits, challenges, and opportunities of theranostic nanoprobes and routes of administration to inform future nanoparticle design.