The ultramafic mantle sections of the Yarlung-Zangbo ophiolites (YZO) along the suture of India and Asia in Tibet preserve the mantle history of the formerly intervening oceanic lithosphere. Fifty-two ophiolitic peridotites from three localities (Purang, Baigang and Zedang) reveal that these rocks comprise Mesozoic depleted mantle (peak mode 187Os/188Os = 0.126), mixed with more ancient mantle domains (187Os/188Os: 0.113–0.121, with model ages up to 2.2 Ga), probably through subduction or delamination of older lithosphere prior to its re-encapsulation into Mesozoic oceanic lithosphere. Whole-rock major and trace elements indicate that this composite mantle lithosphere experienced moderate to high degrees (∼10–30%) of partial melting in the Permian-Triassic, possibly due to the rifting of the back-arc basin in the northern margin of East Gondwana and the opening of Neo-Tethys. However, the generally flat primitive upper mantle-normalized highly siderophile element patterns do not match the depleted lithophile element characteristics. Sub-vertical (Pd/Ir)N-Al2O3 variations, coupled with the occurrence of variable amounts of interstitial base metal sulfides (BMS) and correlations with (Pd/Ir)N and Cu contents, indicate the addition of S-saturated (or BMS-rich) melts or fluids into this oceanic lithosphere. This may have occurred at ∼130–120 Ma during a new episode of Neo-Tethyan subduction, during which S-saturated forearc basaltic magmas were produced and subsequently overprinted the overlying peridotitic lithospheric mantle. The Tibetan YZO illustrate the complex life cycle of ophiolitic peridotites related to multi-stage regional tectonic events, and provide insights into understanding geodynamic mechanisms that have operated in the Earth’s upper mantle.