Watermelon (Citrullus lanatus), a vital economic crop, is severely threatened by Fusarium wilt (FW), which is caused by the soil-borne fungal pathogen Fusarium oxysporum f. sp. niveum (Fon). To elucidate the molecular mechanisms underlying FW resistance in watermelon, we tracked the infection process via microscopy, identifying three critical time points (1, 6, and 8 days post-inoculation) corresponding to spore germination, hyphal invasion of the xylem vascular system, and symptom onset, respectively. Transcriptional profiling at these stages revealed six disease-resistance-associated gene modules through differential expression analysis, expression pattern clustering, weighted gene co-expression network analysis, and functional enrichment. These modules exhibited strong correlations with distinct infection phases. Protein–protein interaction networks identified 35 hub genes, including receptor-like kinases; WRKY and ethylene-responsive factor transcription factors; and genes involved in cell wall reinforcement, hormone signaling, defense metabolism/detoxification, programmed cell death regulation, and antimicrobial compound biosynthesis. Differential expressions of these genes across infection stages likely underpin the observed phenotypic disparities. Five hub regulatory genes were identified by quantitative real-time PCR in the SRgreen and SRblack modules, namely, Cla97C01G014990 (WRKY transcription factor 42), Cla97C02G042360 (calcium-transporting ATPase), Cla97C08G155710 (AIG2), Cla97C09G170380 (ethylene-responsive factor 1B-like), and Cla97C06G121810 (receptor kinase, putative). These genes mediate early rapid defense responses via SRgreen and sustain long-term resistance through SRblack. By validating the expression patterns of hub genes, the study elucidated the watermelon resistance response and provided insights into transcriptional regulation during different stages of Fon–watermelon interactions. Additionally, it identified candidate genes that could enhance watermelon resistance to wilt disease.