Current evidence on the effect of a low-fat (LF) diet on depression scores has been inconsistent. To explore the effect of an LF diet on depression scores of adults by systematic review and meta-analysis of randomized controlled trials (RCTs). The PubMed, ISI Web of Science, Scopus, and CENTRAL databases were searched from inception to June 7, 2023, to identify trials investigating the effect of an LF diet (fat intake ≤30% of energy intake) on the depression score. Random-effects meta-analyses were used to estimate pooled summary effects of an LF diet on the depression score (as Hedges g). Finding from 10 trials with 50 846 participants indicated no significant change in depression score following LF diets in comparison with usual diet (Hedges g = -0.11; 95% CI, -0.25 to 0.03; P = 0.12; I2 = 70.7% [for I2, 95% CI, 44%, 85%]). However, a significant improvement was observed in both usual diet and LF diets when the content of protein was 15-20% of calorie intake (LF, normal protein diet: n = 5, Hedges g = -0.21, 95% CI, -0.24 to -0.01, P = 0.04, I2 = 0%; usual, normal protein diet: n = 3, Hedges g = -0.28, 95% CI, -0.51 to -0.05, P = 0.01, I2 = 0%). Sensitivity analysis also found the depression score improved following LF diet intervention in participants without baseline depression. This study revealed that LF diet may have small beneficial effect on depression score in the studies enrolled mentally healthy participants. Moreover, achieving to adequate dietary protein is likely to be a better intervention than manipulating dietary fat to improve depression scores. However, it is not clear whether this effect will last in the long term. Conducting more studies may change the results due to the low-certainty of evidence. CRD42023420978 (https://www.crd.york.ac.uk/PROSPERO).