Background and Objective Caregiver burden in Parkinson's disease (PD) has been studied in many cross‐sectional studies but poorly in longitudinal ones. The aim of the present study was to analyze the change in burden, strain, mood, and quality of life (QoL) after a 2‐year follow‐up in a cohort of caregivers of patients with PD and also to identify predictors of these changes. Patients and Methods PD patients and their caregivers who were recruited from January/2016 to November/2017 from 35 centers of Spain from the COPPADIS cohort were included in the study. They were evaluated again at 2‐year follow‐up. Caregivers completed the Zarit Caregiver Burden Inventory (ZCBI), Caregiver Strain Index (CSI), Beck Depression Inventory‐II (BDI‐II), and EUROHIS‐QOL 8‐item index (EUROHIS‐QOL8) at baseline (V0) and at 2‐year follow‐up (V2). General linear model repeated measure and lineal regression models were applied. Results Significant changes, indicating an impairment, were detected on the total score of the ZCBI (p < 0.0001), CSI (p < 0.0001), BDI‐II (p = 0.024), and EUROHIS‐QOL8 (p = 0.002) in 192 PD caregivers (58.82 ± 11.71 years old; 69.3% were females). Mood impairment (BDI‐II; β = 0.652; p < 0.0001) in patients from V0 to V2 was the strongest factor associated with caregiver's mood impairment after the 2‐year follow‐up. Caregiver's mood impairment was the strongest factor associated with an increase from V0 to V2 on the total score of the ZCBI (β = 0.416; p < 0.0001), CSI (β = 0.277; p = 0.001), and EUROHIS‐QOL (β = 0.397; p = 0.002). Conclusion Burden, strain, mood, and QoL were impaired in caregivers of PD patients after a 2‐year follow‐up. Mood changes in both the patient and the caregiver are key aspects related to caregiver burden increase. Key points The present study is, to date, the largest prospective longitudinal study conducted for analyzing how burden, strain, mood, and quality of life change (QoL) in the principal caregiver of a patient with Parkinson's disease (PD). After 2 years of follow‐up, the status of the principal caregiver of a patient with PD worsens as a whole with an increase in burden and stress and a worsening in mood and QoL. Mood changes in the patient and in the caregiver as well are key aspects related to increase in caregiver burden. These findings suggest that it could be essential to detect depressive symptoms both in the patient and in the caregiver too.