Natural products have been of much interest in research studies owing to their wide pharmacological applications, chemical diversity, low side effects, and multitarget activities. Examples of these compounds include matrine, sulforaphane, silibinin, curcumin, berberin, resveratrol, and quercetin. Some of the present anticancer drugs, such as taxol, vincristine, vinblastine, and doxorubicin are also derived from natural products. The anti-carcinogenic effects of these products are partly mediated through modulation of microRNA-21 (miR-21) expression. To date, numerous downstream targets of miR-21 have been recognized, which include phosphatase and tensin homolog (PTEN), ras homolog gene family member B (RHOB), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), programmed cell death 4 (PDCD4), signal transducer and activator of transcription (STAT)-3, and nuclear factor kappa B (NF-κB) pathways. These signaling pathways, their regulation by oncomiR-21 in cancer, and the modulating impact of natural products are the main focus of this review.