The mechanism of the combined action of potassium (K) and melatonin (Mel) in modulating tolerance to cadmium (Cd) stress in plants is not well understood. The present study reveals the synergistic role of K and Mel in enhancing physiological and biochemical mechanisms of Cd stress tolerance in tomato seedlings. The present findings reveal that seedlings subjected to Cd toxicity exhibited disturbed nutrients balance [nitrogen (N) and potassium (K)], chlorophyll (Chl) biosynthesis [reduced δ-aminolevulinic acid (δ-ALA) content and δ-aminolevulinic acid dehydratase (δ-ALAD) activity], pathway of carbon fixation [reduced fructose-1,6-bisphosphatase (FBPase) and sedoheptulose-1,7- bisphosphatase (SBPase) activity] and photosynthesis process in tomato seedlings. However, exogenous application of K and Mel alone as well as together improved physiological and biochemical mechanisms in tomato seedlings, but their combined application proved best by efficiently improving nutrient uptake, photosynthetic pigments biosynthesis (increased Chl a and b, and Total Chl), carbon flow in Calvin cycle, activity of Rubisco, carbonic anhydrase activity, and accumulation of total soluble carbohydrates content in seedlings under Cd toxicity. Furthermore, the combined treatment of K and Mel suppressed overproduction of reactive oxygen species (hydrogen peroxide and superoxide), Chl degradation [reduced chlorophyllase (Chlase) activity] and methylglyoxal content in Cd-stressed tomato seedlings by upregulating glyoxalase (increased glyoxalase I and glyoxalase II activity) and antioxidant systems (increased ascorbate-glutathione metabolism). Thus, the present study provides stronger evidence that the co-application of K and Mel exhibited synergistic roles in mitigating the toxic effect of Cd stress by increasing glyoxalase and antioxidant systems and also by improving photosynthetic efficiency in tomato seedlings.