Objectives <p>To evaluate the correlation between time-dependent diffusion MRI (<i>t</i>_<i>d</i>-dMRI) parameters and prognostic factors in nasopharyngeal carcinoma (NPC).</p> Materials and methods <p>116 patients (105 NPC, 11 benign hyperplasia) were prospectively enrolled. Four <i>t</i>_<i>d</i>-dMRI-derived microstructural parameters, extracellular diffusivity (D_ex), intracellular volume fraction (V_in), Diameter, and Cellularity, and apparent diffusion coefficient (ADC) at three oscillation frequencies (ADC_0Hz, ADC_30Hz, and ADC_55Hz), were obtained. TNM stages and prognostic factors were recorded; continuous variables were dichotomized by optimal cut-offs. Correlations, between-group comparisons, and receiver operating characteristic analysis summarized diagnostic performance as the area under the curve (AUC).</p> Results <p>Programmed death ligand 1 was correlated with ADC values, with ADC_55Hz achieving an AUC of 0.708. Epidermal growth factor receptor was correlated with Cellularity and Diameter (r = 0.341 and −0.329). Ki-67 expression was associated with D_ex and ADC_55Hz (r = 0.252 and 0.286). V_in, Cellularity and ADC_0/30Hz were linked to histological subtype, with V_in achieving the highest AUC of 0.706. TNM stages were correlated with Diameter (r = 0.203 to 0.371) and Cellularity (r = −0.365 to −0.284). ADC_30Hz best distinguished NPC (T1–2) from hyperplasia (AUC = 0.847). Negative correlations were observed between several parameters and Epstein-Barr virus (EBV)-based antibodies (r = −0.269 to −0.239). V_in and ADC_0/30Hz differed across EBV DNA clearance groups after induction chemoimmunotherapy (<i>p</i> ≤ 0.038). <i>t</i>_<i>d</i>-dMRI-measured diameters correlated with pathological measurements (r = 0.772, <i>p</i> &lt; 0.001).</p> Conclusions <p><i>t</i>_<i>d</i>-dMRI parameters may reflect tumor microstructure and show associations with prognostic factors in NPC, suggesting potential utility for risk stratification and treatment monitoring.</p> Key Points <p><Emphasis Type="BoldItalic">Question</Emphasis> <i>Can microstructural parameters from time-dependent diffusion MRI (t</i>_<i>d</i><i>-dMRI) noninvasively provide clinically meaningful prognostic information for nasopharyngeal carcinoma?</i></p> <p><Emphasis Type="BoldItalic">Findings</Emphasis> <i>Differences in prognostic factor levels can be reflected by t</i>_<i>d</i><i>-dMRI, and t</i>_<i>d</i><i>-dMRI-derived diameter was correlated with pathology-derived diameter (r = 0.772, p &lt; 0.001).</i></p> <p><Emphasis Type="BoldItalic">Clinical relevance</Emphasis> <i>t</i>_<i>d</i><i>-dMRI provides a noninvasive method to characterize tumor microstructure, potentially improving patient management strategies in nasopharyngeal carcinoma.</i></p> Graphical Abstract <p></p>