Noscapine displays weak anticancer efficacy and numerous research efforts have attempted to generate more potent noscapine analogues. These modifications included the replacement of the N‐methyl group in the 6′‐position with a range of substituents, where N‐ethylcarbamoyl substitution was observed to possess enhanced anticancer activity. Herein, we describe advances in this area, namely the synthesis and pharmacological evaluation of a series of N‐sulfonyl and N‐sulfamoyl noscapine derivatives. A number of these sulfonyl‐containing noscapinoids demonstrated improved activities compared to noscapine. ((R)‐5‐((S)‐4,5‐Dimethoxy‐1,3‐dihydroisobenzofuran‐1‐yl)‐4‐methoxy‐6‐((1‐methyl‐1H‐imidazol‐4‐yl)sulfonyl)‐5,6,7,8‐tetrahydro[1,3]dioxolo[4,5‐g]isoquinoline) (14 q) displayed sub‐micromolar activities of 560, 980, 271 and 443 nM against MCF‐7, PANC‐1, MDA‐MB‐435 and SK‐MEL‐5 cells, respectively. This antiproliferative effect was also maintained against drug‐resistant NCI/AdrRES cells despite high expression of the multidrug efflux pump, P‐glycoprotein