Here, we used RNA sequencing and tandem mass tag (TMT)–based quantitative proteomics technology to study the comprehensive mRNA and protein expression changes during fruit development and ripening in watermelon. A total of 6,226 proteins were quantified, and the number of quantitative proteins is the largest in fruit proteome to date, comparable to studies in model organisms such as rice and Arabidopsis. Omics analysis showed that smaller changes occurred in protein abundance compared to mRNA abundance. Furthermore, protein and transcript abundance were poorly correlated, and the correlation coefficients decreased during fruit development and ripening. Our comprehensive transcriptomic and proteomic data offer a valuable resource for watermelon research, and provide new insights into the molecular mechanisms underlying complex regulatory networks of fruit ripening in watermelon.