Drug-delivery systems, using natural drug carriers, have become increasingly important because of their nontoxicity and biodegradability. In this study, firstly, quaternized carboxymethyl chitosan (QCMC) was intercalated into the interlayer of organic montmorillonite (OMMT) to obtain the QCMC/OMMT nanocomposites, their structure, morphology, and thermal stability were investigated. Next, crosslinked alginate/QCMC/OMMT (AQCOM) microsphere was obtained by crosslinking with CaCl2, and the drug-controlled release behavior was evaluated with bovine serum albumin (BSA) as model drug. The results suggested that, carboxyl groups in alginate and QCMC crosslinked with Ca(2+), quaternary ammonium groups in QCMC or OMMT electrostatically interacted with carboxyl groups in alginate, and there was stable three-dimensional network in AQCOM microsphere. The swelling ratio of AQCOM microspheres decreased with the increase of OMMT content, the lowest one was only about 45% compared to the microsphere without OMMT of 197%. Besides, the in vitro release results for BSA indicated that the AQCOM microsphere displayed more excellent encapsulation and controlled release capacities than the microsphere without OMMT. The in vitro active cutaneous anaphylaxis test was carried out on Guinea pigs, which revealed that AQCOM microsphere did not cause anaphylaxis. Therefore, QCMC/OMMT nanocomposites from natural materials are considerably suitable to apply as drug-controlled release carriers.