Cassava (Manihot esculenta Crantz) is used as biomass energy materials and an effective supplement for food and feed. Cinnamyl alcohol dehydrogenase (CAD) catalyzes the final step of lignin biosynthesis and is responsible for various stresses. However, systematic investigation of CAD gene family in cassava has been poorly understood. In this study, we performed a genome-wide survey and identified 36 MeCADs genes that were unevenly harbored in 12 chromosomes. Through phylogenetic analyses along with Arabidopsis counterparts, these MeCADs were divided into four groups, each gene contains a similar structure and conserved motifs. Interestingly, transcriptome data analyses unveiled 32 MeCAD genes during the postharvest physiological deterioration (PPD) process of cassava tuberous roots, whereas 27 MeCAD genes significantly changed. Meanwhile, the relative quantitative analysis of 6 MeCAD genes demonstrated that they were sensitive to PPD, suggesting they may involve in PPD regulation. Silencing MeCAD13 and MeCAD28 further showed that lignin content significantly decreased in the leaves. The wound-stress tolerance of transgenic yeast cells was enhanced after transformation with MeCAD13 and MeCAD28. In conclusion, MeCAD13 and MeCAD28 may play positive roles in lignin biosynthesis and PPD response, respectively. These results provided a systematic functional analysis of MeCADs in cassava and paved a new way to genetically modify of lignin biosynthesis and PPD tolerance.