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A plant factory with artificial lighting (PFAL) usually uses top lighting for cultivation. The light from the upper part of the canopy cannot penetrate the entire lettuce canopy, however, resulting in uneven vertical spatial light in the canopy, and accelerating the senescence of both the bottom and side leaves of the plant canopy. Therefore, in this study, the performance of lettuce in hydroponics was investigated upon supplemental side lighting with different spectral LEDs in a PFAL. A set of short-term side lighting treatments, including no side lamps (CK), red (R), blue (B), red + blue (RB), and red + blue + green (RGB) LED lamps (150 μmol·m−2·s−1, respectively), was employed for an additional 2 h per day after normal top lighting for 6 days before harvest. The results showed that the lettuce canopy was relatively loose and had a large crown size under side lighting compared with CK. Side lighting, irrespective of spectral qualities, significantly increased the fresh weight, and the R, B, RB, and RGB treatments increased the shoot fresh weight of lettuce plants by 34%, 19%, 31%, and 34%, and increased the fresh weight of leaf layer 2 by 50%, 17%, 44%, and 48%, respectively. The side lighting of different spectral qualities had a significant impact on the nutritional quality of the first row of lettuce at the edge of the top lighting illuminated area. Treatment B significantly promoted the chlorophyll content of leaf layer 3; the soluble sugar contents from leaf layer 1, 2, and 3; the starch contents in leaf layers 2 and 3; and the content of phenolics in the leaf layers 3; and significantly reduced the nitrate content in leaf layers 2 and 3. RGB significantly increased soluble sugar content by 91%, and the starch content in leaf layer 1, as well as the leaf chlorophyll and flavonoid content of leaf layer 3, while R had opposite effect completely. RB significantly increased the leaf chlorophyll content of leaf layer 3 and the nitrate content in leaf layer 1, but the overall effect was lower than that of RGB. In summary, side lighting of any type could effectively improve lettuce yield, solve the problem of inconsistent lettuce plant size caused by the edge effect of top lighting, and affect the nutritional quality of lettuce. B and RGB performed best. There was spatial response diversity of lettuce plants to side lighting spectral qualities.