Drought stress seriously affects tomato growth, yield and quality. Previous reports have pointed out that melatonin (MT) can alleviate drought stress damage to tomato. To better understand the possible physiological and molecular mechanisms, chlorophyll fluorescence parameters and leaf transcriptome profiles were analyzed in the "Micro Tom" tomato cultivar with or without melatonin irrigation under normal and drought conditions. Polyethylene glycol 6000 (PEG6000) simulated continuous drought treatment reduced plant height, but melatonin treatment improved plant growth rate. Physiological parameter measurements revealed that the drought-induced decreases in maximum efficiency of photosystem II (PSII) photochemistry, the effective quantum yield of PSII, electron transfer rate, and photochemical quenching value caused by PEG6000 treatment were alleviated by melatonin treatment, which suggests a protective effect of melatonin on PSII. Comparative transcriptome analysis identified 447, 3982, 4526 and 3258 differentially expressed genes (DEGs) in the comparative groups plus-melatonin vs. minus-melatonin (no drought), drought vs. no drought (minus-melatonin), drought vs. no drought (melatonin) and plus-melatonin vs. minus-melatonin (drought), respectively. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis revealed that DEGs in the four comparative groups were involved in multiple metabolic processes and closely related to hormone signal transduction and transcription factors. Transcriptome data revealed that melatonin changed the expression pattern of most hormone signal transduction related DEGs induced by drought, and improved plant drought resistance by down-regulating the expression of linoleic acid catabolic enzyme genes. These results provide new insights into a probable mechanism of the melatonin-induced protection of photosynthesis and enhancement of drought tolerance in tomato plants.