Aims Soluble guanylyl cyclase (sGC) is a key modulator in the regulation of vascular tone. However, its role and involving mechanism in cholesterol metabolism of macrophages and atherosclerosis remain unclear. Methods Oil red O staining, Dil‐oxidized low‐density lipoprotein (oxLDL)‐binding assay and cholesterol efflux assay were performed in biology of foam cells. Levels of cytokines or intracellular lipid were evaluated by ELISA or colorimetric kits. Expression of gene or protein was determined by quantitative real‐time PCR or Western blotting. Histopathology was examined by haematoxylin and eosin staining. Results Soluble guanylyl cyclase was expressed in macrophages of mouse atherosclerotic lesions. Treatment with 1H‐[1, 2, 4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ, sGC inhibitor) exacerbated oxLDL‐induced cholesterol accumulation in macrophages. In contrast, 3‐(5′‐hydroxymethyl‐2′furyl)‐1‐benzyl indazole (YC‐1, sGC activator) attenuated the oxLDL‐induced cholesterol accumulation because of increased cholesterol efflux. Additionally, YC‐1 dose dependently increased the protein expression of ATP‐binding cassette transporter A1 (ABCA1) but did not alter that of scavenger receptor class A (SR‐A), CD36, SR‐BI or ABCG1. Moreover, YC‐1‐upregulated ABCA1 level depended on liver X receptor α (LXRα). Inhibition of the LXRα‐ABCA1 pathway by LXRα small interfering RNA (siRNA), ABCA1 neutralizing antibody or ABCA1 siRNA abolished the effect of YC‐1 on cholesterol accumulation and cholesterol efflux. In vivo, YC‐1 retarded the development of atherosclerosis, accompanied by reduced serum levels of cholesterol and pro‐inflammatory cytokines, in apolipoprotein E‐deficient mice. Conclusion Activation of sGC by YC‐1 leads to LXRα‐dependent upregulation of ABCA1 in macrophages and may confer protection against atherosclerosis.