Aquatic ecosystems are highly vulnerable to anthropogenic activities. However, it remains unclear how the microbiome responds to press disturbance events in these ecosystems. We examined the impact of the world's largest mining disaster (Brazil, 2015) on sediment microbiomes in two disturbed rivers compared to an undisturbed river during 390 days post-disturbance. The diversity and structure of the virulome and microbiome, and of antibiotic and metal resistomes, consistently differed between the disturbed and undisturbed rivers, particularly at day 7 post-disturbance. 684 different ARGs were predicted, 38% were exclusive to the disturbed rivers. Critical antibiotic resistance genes (ARGs), e.g., mcr and ereA2, were significantly more common in the disturbed microbiomes. 401 different ARGs were associated with mobile genetic elements (MGEs), 95% occurred in the disturbed rivers. While plasmids were the most common MGEs with a broad spectrum of ARGs, spanning 16 antibiotic classes, integrative conjugative elements (ICEs) and integrons disseminated ARGs associated with aminoglycoside and tetracycline, and aminoglycoside and beta-lactam, respectively. A significant increase in the relative abundance of class 1 integrons, ICEs, and pathogens was identified at day 7 in the disturbed microbiomes, 72-, 14- and 3- fold higher, respectively, compared with the undisturbed river. Mobile ARGs associated with ESKAPEE group pathogens, while metal resistance genes and virulence factor genes in nonpathogenic hosts predominated in all microbiomes. Network analysis showed highly interconnected ARGs in the disturbed communities, including genes targeting antibiotics of last resort. Interactions between copper and beta-lactam/aminoglycoside/macrolide resistance genes, mostly mobile and critical, were also uncovered. We conclude that the mud tsunami resulted in resistome expansion, enrichment of pathogens, and increases in promiscuous and mobile ARGs. From a One Health perspective, mining companies need to move toward more environmentally friendly and socially responsible mining practices to reduce risks associated with pathogens and critical and mobile ARGs.