Echinochloa crus-galli is the main weed in direct dry-seeded rice systems worldwide and is the target of most herbicide applications. Numerous cases of E. crus-galli biotypes with resistance to herbicides have been reported in different regions of the world; however, to date, no cases have been reported in Uruguay. The purpose of this research is to assess the presence of herbicide-resistant E. crus-galli in the rice fields of Uruguay. More than 40 E. crus-galli biotypes were sampled from eastern to northern regions in different years and assessed following the Herbicide Resistance Action Committee (HRAC) protocols of confirmation, using the herbicides propanil, quinclorac, clomazone, bispyribac–sodium, penoxsulam, imazapyr + imazapic, profoxidim and cyhalofop. Herbicides rates included 0, 0.125, 0.25, 0.50, 1, 2, 4 and 8 times the label rate. Most E. crus-galli biotypes (35) resulted as resistant to quinclorac. Furthermore, resistance was confirmed to propanil in at least seven biotypes, 12 to imazapyr + imazapic, and three to penoxsulam. Five biotypes showed multiple resistance to propanil and quinclorac, and one biotype was resistant to quinclorac, penoxsulam and imazapyr + imazapic. No biotype showed confirmed resistance to clomazone, bispyribac-sodium, cyhalofop or profoxidim—herbicides that ensure satisfactory control. The presence of E. crus-galli herbicide resistant-biotypes reduces herbicide options, threatening rice production in Uruguay. In this context, a redesign of the productive systems would represent an opportunity to complement the chemical control, integrating larger-scale cultural and management practices.