Growing demand for low-emission and high-efficiency propulsion systems spurs interest in understanding low-temperature and ultra-high-pressure combustion of alternative biofuels like diethyl ether (DEE). In this study, DEE oxidation experiments are performed at 10 and 100 atm, over a temperature range of 400-900 K, at fuel-lean, stoichiometric, and fuel-rich conditions by using a supercritical pressure jet-stirred reactor (SP-JSR). The experimental data show that DEE is very reactive and exhibits an uncommon low-temperature oxidation behavior with two negative temperature coefficient (NTC) zones. The first NTC zone is mainly governed by the competition reactions of QOOH + O 2 = O 2 QOOH and QOOH = 2CH 3 CHO + OH, while the second one is mainly governed by the competition reactions of R + O 2 = RO 2 and the β-scission reaction of fuel radical R. It is shown that the increase of pressure stabilizes RO 2 and promotes HO 2 chemistry. Moreover, the branching ratios of β-scission reactions of R and QOOH decrease. As a result, it is shown that, with the increase of pressure, both NTC zones become weaker at 100 atm. In addition, the intermediate-temperature oxidation is shifted considerably to lower temperature at 100 atm. The existing DEE model in the literature well predicts the experimental data at low temperature; however, it underpredicts the fuel consumptions at intermediate temperature. The H 2 /O 2 subset in the existing DEE model is updated in this study based on the Princeton updated HP-Mech, including the singlet/triplet competing channels of HO 2 related reactions. The updated model improves the overall predictability of key species, especially at intermediate temperature.