Purpose: Osteosarcoma (OS) is the most common primary bone tumor, with high morbidity in infants and adolescents. Long noncodingRNA LINC00313 has been found to modulate papillary thyroid cancer tumorigenesis and to be dysregulate in lung cancer.However, the role of LINC00313 in OS has not yet been addressed. Materials and Methods: We evaluated mRNA and protein expression using real-time quantitative PCR and Western blotting. Cellproliferation was evaluated using MTT; apoptosis and autophagy were assessed with flow cytometry, Western blotting, and/orGFP-LC3 assay. Transwell assay was conducted to measure cell migration and invasion. Potential target sites for LINC00313 andmiR-342-3p were predicted with starBase v.2.0 and TargetScan Human, and verified using luciferase reporter assay, RNA immunoprecipitation,and RNA pull-down assay. In vivo, xenogeneic tumors were induced with U2OS and MG-63 cells, separately. Results: LINC00313 was upregulated and miR-342-3p was downregulated in OS tissues and cells. High expression of LINC00313was associated with shorter overall survival. FOSL2 downregulation and miR-342-3p overexpression suppressed cell proliferationand migratory and invasive abilities while promoting apoptosis and autophagy, all of which were consistent with the effects ofLINC00313 knockdown. miR-342-3p, sponged by LINC00313, inversely modulated FOSL2 by targeting MG-63 cells, and FOSL2expression was positively controlled by LINC00313. LINC00313 knockdown suppressed tumor growth in vivo. Conclusion LINC00313 is upregulated in OS, and LINC00313 knockdown plays a vital anti-tumor role in OS cell progressionthrough a miR-342-3p/FOSL2 axis. Our study suggests that LINC00313 may be a novel, promising biomarker for diagnosis andprognosis of OS.