Objective To analyze the direct economic burden of elderly patients with healthcare-associated infection (HAI) caused by multidrug-resistant ogranism (MDRO), and provide evidence-based support for constructing precise prevention and control strategies. Methods Data of elderly patients with MDRO HAI from January 2023 to December 2024 in a tertiary first-class hospital were collected. After using propensity score matching (PSM) to balance confounding factors among groups, differences in length of hospital stay and total expense between MDRO group and non-MDRO group were compared. Results A total of 234 patients were included in analysis, with 75 in MDRO group and 75 in non-MDRO group after PSM. Univariate analysis showed that MDRO group were all higher than non-MDRO group in terms of mechanical ventilation, histories of recent medical exposure, antimicrobial exposure, and invasive procedure history, as well as antimicrobial resistance rate (all P<0.05). In terms of economic burden, length of hospital stay in MDRO group was longer than non-MDRO group (25 vs 22 days; U=2 249.5, P=0.034), and the median of total expense was also higher (37 779.0 vs 15 075.7 Yuan; U=1 832.5, P＜0.001). Except for self-paid hospitalization expense and surgical treatment expense, other expense in MDRO group were all higher than non-MDRO group (all P<0.05). In terms of infection site, MDRO group had higher economic burden on respiratory tract and urinary tract infections than non-MDRO group (both P<0.05). Gamma regression analysis showed that MDRO infection (OR=1.76, 95%CI: 1.10-2.89), Acinetobacter baumannii infection (OR=1.53, 95%CI: 1.04-2.28), length of hospital stay (OR=1.02, 95%CI: 1.01-1.04), and admission to intensive care unit (ICU) (OR=1.76, 95%CI: 1.13-2.74) were all independent factors affecting medical expense (all P<0.05). Quantile regression revealed that MDRO infection presented positive effect at the low and middle percentile (τ=0.25, β=14 409.75; τ=0.50, β=17 436.48). Length of hospital stay (τ=0.50, β=1 423.15; τ=0.75, β=1 176.13) and admission to ICU (τ=0.50, β=25 762.75; τ=0.75, β=51 689.76) increased the expense at the middle and high percentile (both P<0.05). Conclusion MDRO HAI bring about heavy economic burden on elderly patients. Medical institutions should establish an integrated system that integrates antimicrobial management, early diagnosis, and key prevention and control, so as to effectively control medical expense through multidisciplinary quality improvement.