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This study delved into the impact of two extrusion processing parameters—screw speed (<i>SS</i> at 400, 600, 800 RPM) and material moisture content in the extruder barrel (<i>M</i> at 12, 15, 18%) at constant feed rate (50 kg/h)—on reducing the content of alternariol (AOH), alternariol monomethyl ether (AME), tenuazonic acid (TeA), and tentoxin (TEN) in whole-grain red sorghum flour. Ultra-performance liquid chromatography combined with a triple-quadrupole mass spectrometer (UPLC-MS/MS) was employed for the determination of <i>Alternaria</i> toxin levels. The extruder die temperature fluctuated between 136 and 177 °C, with die pressures ranging from 0.16 to 6.23 MPa. The specific mechanical energy spanned from 83.5 to 152.3 kWh/t, the torque varied between 88 and 162.8 Nm, and the average material retention time in the barrel ranged from 5.6 to 13 s. The optimal parameters for reducing the concentration of all <i>Alternaria</i> toxins with a satisfactory quality of the sorghum snacks were: <i>SS</i> = 400 RPM, <i>M</i> = 12%, with a reduction of 61.4, 76.4, 12.1, and 50.8% for AOH, AME, TeA, and TEN, respectively.