Background/Objectives: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss, oxidative stress, and mitochondrial dysfunction. Although levodopa (L-Dopa) remains the main symptomatic treatment, prolonged administration can lead to adverse effects. Safranal, a bioactive constituent of Crocus sativus, has antioxidant and anti-apoptotic properties. This study evaluated the neuroprotective potential of L-Dopa and safranal, individually and in combination, in an in vitro cell-culture PD model. Methods: SH-SY5Y human neuroblastoma cells were treated with 6-hydroxydopamine (6-OHDA, 50 µM) to induce cytotoxicity. Cells were pretreated with L-Dopa (5-500 µM) and safranal (1-500 µM and 1-5 mM) for 4 or 24 h. Cell viability was assessed using 3-(4, 5-dimethylthiazol-2-yl)2,5-diphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Mitochondrial membrane potential (MMP), caspase-3/7 activity, and autophagy markers were also evaluated. Synergy was analyzed using Combination Index (CI) analysis. Furthermore, mRNA levels of circadian rhythm associated genes were also evaluated. Results: 6-OHDA significantly impaired cell viability and mitochondrial function. Pretreatment with low doses of L-Dopa and safranal partially improved cell viability and reduced apoptosis and showed a tendency to decrease autophagy-associated marker levels. Higher L-Dopa concentrations caused mild cytotoxicity, while high-dose safranal exhibited pronounced concentration-dependent toxicity. CI analysis confirmed synergistic interaction between both drugs in mitigating 6-OHDA-induced toxicity. Combined treatment markedly improved cell survival preserved mitochondrial function, and reduced caspase-3/7 activity compared with monotherapy. A significant increase in the mRNA levels of Per1, Clock, Bmal1 and Cry1 genes was observed in groups treated with L-Dopa and safranal together. Conclusions: L-Dopa and safranal exerted concentration-dependent neuroprotective effects in SH-SY5Y cells. Their combination enhanced cytoprotection, which was associated with modulation of mitochondrial function, oxidative stress, apoptosis, and autophagy-related responses.