Chronic pain conditions such as fibromyalgia (FM) and temporomandibular disorders (TMDs) are accompanied by complex interactions of cognitive, emotional, and physiological disturbances. Such conditions are complicated and draining to live with, and successful adaptation may depend on ability to self-regulate. Self-regulation involves capacity to exercise control and guide or alter reactions and behavior, abilities essential for human adjustment. Research indicates that self-regulatory strength is a limited source that can be depleted or fatigued, however, and the current study aimed to show that patients with FM and TMD are vulnerable to self-regulatory fatigue as a consequence of their condition. Patients (N = 50) and pain-free matched controls (N = 50) were exposed to an experimental self-regulation task followed by a persistence task. Patients displayed significantly less capacity to persist on the subsequent task compared with controls. In fact, patients exposed to low self-regulatory effort displayed similar low persistence to patients and controls exposed to high self-regulatory effort, indicating that patients with chronic pain conditions may be suffering from chronic self-regulatory fatigue. Baseline heart rate variability, blood glucose, and cortisol predicted persistence, more so for controls than for patients, and more so in the low vs. high self-regulation condition. Impact of chronic pain conditions on self-regulatory effort was mediated by pain, but not by any other factors. The current study suggests that patients with chronic pain conditions likely suffer from chronic self-regulatory fatigue, and underlines the importance of taking self-regulatory capacity into account when aiming to understand and treat these complex conditions.