Lettuce (Lactuca sativa) is among the most consumed vegetables worldwide and is primarily field-grown; however, indoor agriculture enables year-round, precise production. Through precise manipulation of the mean daily temperature (MDT) and photosynthetic photon flux density (PPFD), crop color, morphology, and yield can be altered. Therefore, we quantified how MDT and PPFD interact and developed models predicting yield and economic viability. Eleven days after sowing, green butterhead lettuce ‘Rex’ and red oakleaf lettuce ‘Rouxaï RZ’ were transplanted into six deep-flow hydroponic tanks with day/night and MDTs of 22/15 °C (20 °C), 25/18 °C (23 °C), or 28/21 °C (26 °C), under light-emitting diodes providing a low or high PPFD of 150 or 300 µmol·m−2·s−1 for 17-h·d−1. As PPFD increased, shoot fresh mass (SFM) of ‘Rex’ increased by 29% (33.4 g). SFM of ‘Rouxaï RZ’ and shoot dry mass (SDM) of both cultivars was influenced by the interaction of MDT and PPFD. The greatest ‘Rouxaï RZ’ SFM (158.8 g) and SDM (6.42 g) were recorded at >20 °C MDT under the high PPFD; the lowest SFM (76.0 g) and SDM (3.17 g) occurred at 20 °C under the low PPFD. Similarly, ‘Rex’ SDM was greatest (7.36 g) and lowest (3.78 g) under the aforementioned MDTs and PPFDs. Increasing from the low to high PPFD increased tipburn incidence on ‘Rouxaï RZ’ from 0 to 25% and ‘Rex’ from 47 to 100%. ‘Rouxaï RZ’ had darker yellow-red foliage at lower MDTs under the high PPFD. A high MDT and low PPFD resulted in a lighter green. Finally, for the greatest SFM, while reducing energy costs as interpreted from the economic analysis, we recommend growing ‘Rex’ and ‘Rouxaï RZ’ under a PPFD of 150 and 300 µmol·m−2·s−1, respectively, at an MDT of 23 to 26 °C depending on the cost of temperature control.