Background Down syndrome (DS) is associated with early development of Alzheimer’s disease pathology. Both the severity of tau pathology and the increase of neurofilament light chain (NfL) protein are correlated with cognitive decline in the neurotypical populations. Here, we assessed whether tau accumulation in the hippocampus and entorhinal cortex and plasma NfL concentrations were associated with memory performance in adults with DS. Method We used 18F‐AV‐1451 (FTP) positron emission tomography (PET) to assess tau accumulation in 44 participants enrolled in the multi‐site Alzheimer’s Disease in Down syndrome (ADDS) study (age 50.72 + 6.21). FTP‐PET scans were partial volume‐corrected, and weighted standardized uptake value ratio (SUVR) were calculated for each of the following regions of interests (ROIs): entorhinal cortex, hippocampus, and the precentral gyrus (control). Participants' plasma NfL concentration (in pg/mL) was measured on a single plex plate using the ultra‐sensitive single molecule array (Simoa) technology platform HD‐X. Memory performance was measured with the modified Cued Recall Test. We evaluated the relationship between FTP SUVRs, NfL, and memory performance using linear regression analysis. Sex and site were used as covariates. Result Increased FTP SUVR in the hippocampus and entorhinal cortex were associated with lower scores on free recall (hippocampus: r2 = 0.53, p <0.001; entorhinal: r2 = 0.35, p <0.001) and total recall (hippocampus: r2 = 0.46, p <0.001; entorhinal: r2 = 0.29, p <0.01). As expected, no association between FTP SUVRs and memory performance was found in the precentral gyrus. Additionally, higher plasma NfL concentrations were associated with lower free recall (r2 = 0.35, p <0.001) and total recall (r2 = 0.29, p <0.01). Further, increased levels of plasma NfL were associated with increased FTP SUVRs in the hippocampus (r2 = 0.38, p <0.001), entorhinal cortex (r2 = 0.28, p<0.01), and precentral gyrus (r2 = 0.19, p<0.05). Conclusion Increased levels of both in‐vivo tau in medial temporal ROIs and NfL in plasma were associated with worse memory performance, consistent with observations in the neurotypical population. Future work will investigate the impact of tau accumulation and NfL concentration on longitudinal cognitive decline in older adults with DS.