Synthesis of 5‐alkynyl furopyrimidine nucleoside analogs, with free‐ribose groups, was carried out, and their biological activity was evaluated. The substituents introduced at the C‐5 included propargyl and homopropargyl alcohols, 4‐methylphenyl (p‐tolyl), and 4‐pentylphenyl substituted alkynyl groups (56%–88%). Subsequently, alkyne function was coordinated to dicobalt hexacarbonyl unit, yielding the corresponding dicobalt hexacarbonyl 5‐alkynyl furopyrimidine nucleosides (51%–75%). All compounds contained 4‐pentylphenyl group attached at the C‐6 position of the bicyclic base, in line with most active antiviral structures. The antiproliferative effect of these modified nucleosides on cancer cells of different phenotypes was determined using in vitro studies. The tested compounds show antiproliferative effects with median inhibitory concentration (IC50) values of 16–23 and 9–15 μM for HeLa and K562 cells, respectively. The determination of reactive oxygen species (ROS) formation in K562 cells in the presence of modified nucleosides may suggest that the mode of action of the examined compounds may be attributed to the induction of oxidative stress.