Guayule (Parthenium argentatum) is a woody desert shrub cultivated in the southwestern United States as a source of natural rubber, organic resins, and high energy biofuel feedstock from crop residues. We used guayule bagasse, the residual biomass after latex extraction as feedstock in a pyrolysis process that employs a reactive gas environment to formulate a special intermediate bio-oil product that allows use of conventional hydrotreating with conventional noble metal catalysts and a simple distillation process to synthesize hydrocarbon (drop-in) fuels. The said guayule-bagasse tail gas reactive pyrolysis (TGRP) process comprises pyrolyzing the guayule bagasse in a fluidized-bed reactor in the presence of a reactive and flammable tail gas (comprising CO ∼ 30%, CH4 ∼ 16%, CO2 ∼ 40%, H2 ∼ 10%, C2H4 ∼ traces) generated in the pyrolysis process and without the use of catalyst to produce bio-oil with C/O molar ratio of 14/1 in organic yields of 34–40 wt% having an energy content of 31–37.5 MJ/kg. When we further processed the said bio-oil by centrifugation, we obtained 85 wt% yield and further 50–65 wt% yields following a continuous hydrotreatment over common noble metals (Pt, Ru or Pd) on a carbon support. Distillation of this mixture yielded >95 wt% hydrocarbon liquid fuel mixture comprising 30.4% gasoline (C5–C7), 37% jet (C8–C12) and 24% diesel (C13–C22). Analysis of a composite mixture of the hydrotreated product from the bagasse showed the majority of the sample (66%) was C12 and below, which falls within the gasoline (naphtha) range with the greatest fraction of naphtha falling within the C8–C10 range. Beyond C12, the molecular weights increased through the diesel range (34%), with C37 being the highest observable molecular weight. The product met several ASTM standards for drop-in fuels, but the sulfur content (primarily due to latex extraction additives) was relatively high at around 300 ppm, indicating that hydrodesulfurization may be required to be infrastructure ready.