The development of insecticide resistance in malaria vectors is of increasing concern in Ethiopia because of its potential implications for vector control failure. To better elucidate the specificity of resistance mechanisms and to facilitate the design of control strategies that minimize the likelihood of selecting for cross-resistance, a whole transcriptomic approach was used to explore gene expression patterns in a multi-insecticide resistant population of Anopheles arabiensis from Oromia Region, Ethiopia. This field population was resistant to the diagnostic doses of malathion (average mortality of 71.9%) and permethrin (77.4%), with pools of survivors and unexposed individuals analyzed using Illumina RNA-sequencing, alongside insecticide susceptible reference strains. This population also demonstrated deltamethrin resistance but complete susceptibility to alpha-cypermethrin, bendiocarb and propoxur, providing a phenotypic basis for detecting insecticide-specific resistance mechanisms. Transcriptomic data revealed overexpression of genes including cytochrome P450s, glutathione-s-transferases and carboxylesterases (including CYP4C36, CYP6AA1, CYP6M2, CYP6M3, CYP6P4, CYP9K1, CYP9L1, GSTD3, GSTE2, GSTE3, GSTE4, GSTE5, GSTE7 and two carboxylesterases) that were shared between malathion and permethrin survivors. We also identified nineteen highly overexpressed cuticular-associated proteins (including CYP4G16, CYP4G17 and chitinase) and eighteen salivary gland proteins (including D7r4 short form salivary protein), which may be contributing to a non-specific resistance phenotype by either enhancing the cuticular barrier or promoting binding and sequestration of insecticides, respectively. These findings provide novel insights into the molecular basis of insecticide resistance in this lesser well-characterized major malaria vector species.ImportanceInsecticide-resistant mosquito populations remain a significant challenge to global malaria vector control. While substantial progress has been made unraveling resistance mechanisms in major vector species, such as Anopheles gambiae and An. funestus, comparatively less is known about An. arabiensis populations. Using a whole transcriptomic approach, we investigated genes associated with resistance to insecticides used to control An. arabiensis in Ethiopia. Study findings revealed shared detoxification genes between organophosphate- and pyrethroid-resistant vectors and highly overexpressed cuticular-associated proteins and salivary gland proteins, which may play a role in enhancing insecticide resistance. The whole transcriptomic analysis detected novel resistance-associated genes, which warrant functional validation to determine their specificity to particular insecticides and their potential to confer cross-resistance between different insecticides with the same mode of action. These genes may contribute to the development of diagnostic markers to monitor insecticide resistance dynamics in the field.