There are engineering and payload advantages in growing plants under hypobaric (reduced atmospheric pressure) conditions in biomass production for extraterrestrial base or spaceflight environments. Objectives of this research were to characterize the influence of hypobaria on growth, gas exchange, and ethylene evolution of lettuce (Lactuca sativa L. cv. Buttercrunch). Elevated levels of the plant hormone, ethylene, occur in enclosed crop production systems and in space-flight environments—leading to adverse plant growth and sterility. Lettuce plants were grown under variable total gas pressures [25 (low) or 101 kPa (ambient)]. During short growth periods of up to 10 days, growth was comparable between low and ambient pressure plants. Regardless of total pressure, plant growth was reduced at 6 kPa pO2 compared to 12 and 21 kPa pO2. At 6 kPa pO2 there was greater growth reduction and stress with ambient (101 kPa) than low (25kPa) pressure plants. Plants at 25/12 kPa pO2 had comparable CO2 assimilation and a 25% lower dark-period respiration than 101/21 kPa pO2 (ambient) plants. Greater efficiency of CO2 assimilation/dark-period respiration occurred with low pressure plants at 6 kPa pO2. Low pressure plants had a reduced CO2 saturation point (100 Pa CO2) compared with ambient (150 Pa CO2). Low pO2 lowered CO2 compensation points for both 25 and 101 kPa plants, i.e., likely due to reduced O2 competing with CO2 for Rubisco. Ethylene was 70% less under low than ambient pressure. High ethylene decreased CO2 assimilation rate of 101/12 kPa O2 plants. The higher dark-period respiration rates (higher night consumption of metabolites) of ambient pressure plants could lead to greater growth (biomass production) of low pressure plants during longer crop production cycles.