Background <p>Epidermal growth factor (EGF) has been shown to have neuroprotective effects in Parkinson’s disease (PD). However, there is a lack of research on the association between plasma EGF levels and cognitive impairments in PD patients.</p> Methods <p>The study included 135 PD patients. Plasma EGF concentrations were measured. PD patients without cognitive impairment were followed up for clinical assessment at an average of 2 ± 0.6 years.</p> Results <p>PD patients with cognitive impairment (PD-CI) had lower baseline plasma EGF concentrations compared to PD patients without cognitive impairment. Linear regression analysis demonstrated a significant correlation between baseline plasma EGF concentrations and baseline Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST) scores in PD patients. However, no significant association was found between plasma EGF concentrations and Hopkins Verbal Learning Test-Delayed Recall (HVLT-DR), Semantic Fluency Test (SFT), Clock Drawing Test (CDT), Trail Making Test (TMT) A, or TMT B scores. Furthermore, logistic regression analysis revealed that baseline plasma EGF concentrations were associated with cognitive decline in PD patients without cognitive impairment in adjusted regression models (HR 0.977, 95% CI 0.955–0.999, <i>p</i> = 0.045), after adjusting for various factors. The area under the curve (AUC) for cognitive decline at follow-up time was 0.704 (95% CI 0.600-0.809), and the optimal cut-point for baseline plasma EGF concentrations was determined to be 49.56 pg/mL, with a sensitivity of 49.3% and specificity of 92.3%.</p> Conclusions <p>In conclusion, our study found a correlation between baseline plasma EGF concentrations and cognitive dysfunction in PD.</p>