Fatigue of temporomandibular joint (TMJ) tissues reflects the effects of magnitude (energy density; ED) and frequency of loading (jaw muscle duty factor; DF). This observational study measured these variables and tested for differences in mechanobehavior scores (MBS = ED2 × DF) and component variables in subjects with and without TMJ disc displacement (±D). In accordance with Institutional Review Board and STROBE guidelines, written informed consent was obtained, and examination and imaging protocols identified eligible adult subjects. Specifically, magnetic resonance imaging was used to assign subjects’ TMJs to ±D groups. Subjects were trained to record in-field jaw muscle activities, from which DFs (percentage of recording time) were determined. EDs (mJ/mm3) were estimated using modeled TMJ loads and in vivo dynamic stereometry. Multivariate analysis of variance, post hoc independent t tests, and K-means cluster analysis identified significant group differences (P < 0.05). Of 242 individuals screened, 65 females (TMJs: 78 +D, 52 −D) and 53 males (TMJs: 39 +D, 67 −D) participated. Subjects produced 312 daytime and 319 nighttime recordings of average duration 6.0 ± 0.2 h and 7.6 ± 0.1 h, respectively, and 219 (114 right, 105 left) intact dynamic stereometry recordings. Average EDs were 2-fold and significantly larger in +D than −D TMJs (P < 0.0001). DFs were on average 3-fold larger during the daytime versus nighttime for both masseter and temporalis muscles and 1.8- and 3.0-fold larger for the masseter versus temporalis muscle during the daytime and nighttime, respectively. Daytime masseter MBSs for +D TMJs in females were the largest overall at 621 ± 212 (mJ/mm3)2% and 2- to 43-fold larger versus −D TMJs in both sexes during daytime and nighttime. Cluster analysis (P < 0.0001) identified groups 2 and 3, which comprised 87% +D TMJs and had average MBSs 21-fold larger than group 1. The results show MBS as a potential biomarker to predict homeostasis versus progression or reversal of degenerative TMJ structural changes.