Bladder cancer (BC) is the second most common genitourinary malignancy. Long noncoding RNA (lncRNA) is implicated in BC progression. This study delved into the underlying mechanism of lncRNA MEG3 in BC. Bioinformatics analysis predicted the expression of lncRNA MEG3, its association with the survival of BC patients, its subcellular localization, and its binding sites with miR-21-5p. Differentially expressed genes (DEGs) in the GSE13507 chip were analyzed using GEOexplorer, downstream targets of miR-21-5p were predicted from databases, and the overlapping genes were analyzed by the website Venny2.1 (https://bioinfogp.cnb.csic.es/tools/venny/index.html); their impacts on patient survival were analyzed by the Starbase database. The expression of SPRY2 and TGFBI associated with patient survival was analyzed in TCGA. RT-qPCR and western blot were performed to detect levels of MEG3, miR-21-5p, and SPRY2 in BC/SV-HUC-1 cells. Malignant biological behaviors of BC cells were detected using CCK8, flow cytometry, and Transwell assays. RNA pull-down and dual-luciferase assays were employed to verify the binding relationship of miR-21-5p with MEG3 and SPRY2. MEG3 was found to be lowly expressed in BC cells and mainly distributed in the cytoplasm. Over-expression of MEG3 was found to inhibit BC cell activity, promote apoptosis, and reduce invasion and migration. miR-21-5p was found to be highly expressed in BC cells, and its down-regulation was found to inhibit the malignant behavior of BC cells. Over-expression of miR-21-5p was found to reverse the effect of pcDNA3.1-MEG3 on BC cells. MEG3 was found to competitively bind to miR-21-5p as a ceRNA to promote SPRY2 levels. LncRNA MEG3 promotes SPRY2 expression by competitively binding to miR-21-5p, thereby inhibiting proliferation and promoting apoptosis of BC cells.