Despite recent scientific headway in deciphering maize (Zea mays L.) drought stress responses, the overall picture of key proteins and genes, pathways, and protein–protein interactions regulating maize filling-kernel drought tolerance is still fragmented. Yet, maize filling-kernel drought stress remains devastating and its study is critical for tolerance breeding. Here, through a comprehensive comparative proteomics analysis of filling-kernel proteomes of two contrasting (drought-tolerant YE8112 and drought-sensitive MO17) inbred lines, we report diverse but key molecular actors mediating drought tolerance in maize. Using isobaric tags for relative quantification approach, a total of 5175 differentially abundant proteins (DAPs) were identified from four experimental comparisons. By way of Venn diagram analysis, four critical sets of drought-responsive proteins were mined out and further analyzed by bioinformatics techniques. The YE8112-exclusive DAPs chiefly participated in pathways related to “protein processing in the endoplasmic reticulum” and “tryptophan metabolism”, whereas MO17-exclusive DAPs were involved in “starch and sucrose metabolism” and “oxidative phosphorylation” pathways. Most notably, we report that YE8112 kernels were comparatively drought tolerant to MO17 kernels attributable to their redox post translational modifications and epigenetic regulation mechanisms, elevated expression of heat shock proteins, enriched energy metabolism and secondary metabolites biosynthesis, and up-regulated expression of seed storage proteins. Further, comparative physiological analysis and quantitative real time polymerase chain reaction results substantiated the proteomics findings. Our study presents an elaborate understanding of drought-responsive proteins and metabolic pathways mediating maize filling-kernel drought tolerance, and provides important candidate genes for subsequent functional validation.