The paper aimed to reveal the impacts and the possible mechanism of action of lectin mannose-binding 2 protein (LMAN2) in HER2-positive breast cancer (BC). The expression, prognostic potential of LMAN2, and the correlation between LMAN2 and HEAT repeat containing 3 (HEATR3) in BC were analyzed in TCGA database. Intact, Mentha, and BioGrid databases predicted LMAN2-HEATR3 interactions. Reverse transcription-quantitative PCR and Western blot examined LMAN2 expression. Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine staining, wound healing, and transwell assays, respectively, detected the aggressive cellular biological behaviors including proliferation, migration, and invasion. Western blot analyzed the expression of matrix metalloproteinases, HEATR3, and protein kinase B (Akt)/extracellular signal-regulated kinase (ERK)/nuclear factor-kappaB (NF-κB) signaling-related proteins. Co-immunoprecipitation assay was used to prove the relationship of LMAN2 with HEATR3. Enzyme-linked immunosorbent assay detected inflammatory cytokine levels. LMAN2 was overexpressed in HER2-positive BC tissues and cells and indicated unfavorable prognosis of BC patients. LMAN2 knockdown suppressed HER2-positive BC cell proliferation, migration, and invasion. LMAN2 interacted with and had a positive correlation with HEATR3. HEATR3 up-regulation reversed the repressive role of LMAN2 interference in the progression of HER2-positive BC, Akt/ERK/NF-κB signaling, and inflammatory response. Altogether, LMAN2 silencing might exert anti-tumor and anti-inflammatory properties and inactivate Akt/ERK/NF-κB signaling in HER2-positive BC via binding to HEATR3.