AIMS: Fertilizers can significantly influence leaf senescence and hormonal regulation, which in turn impacts crop yield. Despite significant advancements in understanding fertilizer effects on plant growth, the specific molecular mechanisms through which fertilizers influence hormonal regulation and leaf senescence, and subsequent impact on yield, remain underexplored. This study addresses this critical gap by examining transcriptional, physiological, and molecular mechanisms in the semiarid regions of rainfed spring maize under long-term fertilizers. METHODS: Fertilizer treatments include no amendment (NA), inorganic fertilizer (CF), combined inorganic and organic fertilizer (SC), organic fertilizer (SM), and maize straw (MS) replicated three times. RESULTS: The highest number of differentially expressed genes (DEGs) were observed under CF (3972) followed by SC (1949) in comparison to NA, showing a strong effect of inorganic fertilizer on gene expressions. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that numerous genes involved in the biosynthesis of secondary metabolites, plant hormone signaling, photosynthesis pathways, and metabolic pathways showed varied expressions of up- and downregulation. Genes involved in the ethylene, abscisic acid, jasmonic acid, salicylic acid, and brassinosteroid pathways indicated their interaction and promoted leaf senescence, whereas those related to auxin and gibberellin pathways had minimal impact. In the ethylene pathway known to influence senescence, two ethylene receptor (ETR) genes (Zm00001d013486 and Zm00001d021687) were downregulated, whereas, two ethylene-insensitive proteins 3 (EIN2) genes (Zm00001d053594 and Zm00001d033625) showed upregulation in the CF, SC and SM treatments. Furthermore, 86 highly up-regulated genes involved in the photosynthesis pathway encompassing components such as photosynthesis antenna, photosynthesis complexes II, cytochrome complexes, photosynthesis electron transport, and ATP complex in SC and CF compared to SM and MS. CONCLUSION: In summary, the study finds that DEGs showed stronger responses to inorganic fertilizers, likely due to organic fertilizers decomposing at a slower rate. Nevertheless, transcriptional and physiological analyses indicate that the SC treatment sustainably enhances maize productivity without causing adverse environmental effects, outperforming the other treatments (NA, CF, SM, MS). These results provide new perspectives on genetic regulation and pathway discovery in rainfed maize cultivation in semiarid areas.