<p>Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized primarily by the irreversible loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Although its etiology is complex, mitochondrial dysfunction has been widely recognized as a central hub in the pathogenesis of PD. Concurrently, neurotrophic factors (NTFs), particularly glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) and cerebral dopamine neurotrophic factor (CDNF), which exhibit specific trophic effects on dopaminergic neurons, play a crucial role in the endogenous neuroprotective system. This review aims to move beyond simple mechanistic descriptions and critically analyze the interaction of the “NTFs-mitochondria axis” in PD. We will systematically examine experimental evidence supporting the role of this axis (from in vitro to in vivo models) and clarify its strengths and limitations. Emphasis is placed on the fundamental translational challenges revealed by GFLs-based clinical trials (such as GDNF and neurturin [NRTN]), including delivery bottlenecks, treatment timing, and limitations of disease models. Finally, we evaluate the potential and obstacles of novel strategies targeting this axis (such as new viral vectors, small molecule agonists, mitochondria-targeted drugs, and combination therapies). A deep understanding and addressing the dysregulation of the NTFs-mitochondrial network holds promise for opening new avenues in the development of disease-modifying therapies, but it is essential to remain keenly aware of existing challenges.</p>