This study aimed at investigating the effects of curcumin on tau pathology and neuron loss in late stage, tangle bearing hTau mouse model of tauopathy. Curcumin treatment was found to selectively suppress levels of soluble tau dimers, but not insoluble and monomeric phospho-Tau, In addition curcumin corrected behavioral, synaptic, and deficits in heat shock protein (HSP) expression. Curcumin treatment elevated HSP90 and HSC70 without increasing HSP mRNAs; that is, without induction of the heat shock response. Curcumin treatment differentially impacted HSP90 client kinases, reducing Fyn kinase without reducing Akt kinase. In summary, intervention with curcumin at late stage in tangle-bearing mice reduced soluble Tau oligomers and Fyn kinase, perhaps through increasing HSP70, HSP90, and HSC70, which have the potential to clear misfolded Tau.