Ocean acidification and warming are affecting polar regions with particular intensity. Rocky shores of the Antarctic Peninsula are dominated by canopy-forming Desmarestiales. This study investigates the physiological and transcriptomic responses of the endemic macroalga Desmarestia anceps to a combination of different levels of temperature (2 and 7 °C), dissolved CO2 (380 and 1000 ppm), and irradiance (65 and 145 µmol photons m−2 s−1). Growth and photosynthesis increased at high CO2 conditions, and strongly decreased at 2 °C plus high irradiance, in comparison to the other treatments. Photoinhibition at 2 °C plus high irradiance was evidenced by the photochemical performance and intensive release of dissolved organic carbon. The highest number of differentially regulated transcripts was observed in thalli exposed to 2 °C plus high irradiance. Algal 13C isotopic discrimination values suggested an absence of down-regulation of carbon-concentrating mechanisms at high CO2. CO2 enrichment induced few transcriptomic changes. There was high and constitutive gene expression of many photochemical and inorganic carbon utilization components, which might be related to the strong adaptation of D. anceps to the Antarctic environment. These results suggest that increased temperature and CO2 will allow D. anceps to maintain its productivity while tolerating higher irradiances than at present conditions.