<p>Orphan diseases comprise a range of disorders that individually affect a small percentage of people, but collectively impact millions of people worldwide. Patients with this disorder often face significant challenges in diagnosis, treatment, and access to care due to their rare nature and limited understanding and treatment options. In recent years, significant advancements have been made in the global healthcare in addressing the accessibility of essential treatments and medicines, but still challenges persist particularly related to orphan drugs (to treat rare diseases) in the developing world. The accessibility of orphan drugs remains a major challenge, where patients face barriers such as high costs, limited availability, and inadequate healthcare infrastructure. The high cost associated with orphan drugs presents a barrier to affordability for both patients and healthcare systems, causing disparities in access to life-saving treatments. The molecular farming approach utilizing plant-based production systems for recombinant protein production offers a hope for overcoming barriers to orphan drug access in resource-constrained settings. Molecular farming has the potential to produce a wide range of therapeutic proteins and biologics for the treatment of various rare diseases. The FDA approval of plant-derived proteins for the treatment of Gaucher disease (Elelyso) and Fabry disease (Elfabrio) highlights the potential of plant-based expression systems for the development of suitable drugs targeting niche and orphan diseases. This review examines the potential of the plant system in producing orphan drugs and also highlights the opportunities and challenges related to orphan drug manufacturing.</p>