Frequency of tuberculosis is progressively increasing worldwide. New emerging strains of bacilli that are emerging are resistant to the currently available drugs which make this issue more alarming. In this regard, a series of substituted quinolinyl chalcones, quinolinyl pyrimidines, and pyridines were synthesized and evaluated for their antitubercular activity in vitro against Mycobacterium tuberculosis H37RV. To establish the role of the 2-chloroquinoline nucleus as a pharmacophoric group and study its influence on the antimycobacterial activity, a 3D-QSAR study based on CoMFA and CoMSIA was undertaken on this set of 2-chloroquinoline derivatives. Statistically significant models that are able to well correlate the antimycobacterial activity with the chemical structures of the 2-chloroquinolines have been developed. The contour maps resulting from the best CoMFA and CoMSIA models were used to identify the structural features relevant to the biological activity in this series of analogs. Further analysis of these interaction-field contour maps also showed a high level of internal consistency. The information obtained from the field 3-D contour maps may be fruitfully utilized in the design of more potent 2-chloroquinoline-based analogs as potential antitubercular candidates.