A series of 1,3-diaryl-2-propen-1-ones was synthesized by both the conventional and microwave irradiation methods. It was observed that a microwave-assisted method was a convenient, rapid, and high yielding method for the synthesis of 1,3-diaryl-2-propen-1-ones as compared to the conventional method. In vivo acute toxicity studies and analgesic and anti-inflammatory activities of these compounds were also evaluated. The analgesic activity was evaluated using acetic acid-induced writhing method in mice and aspirin as the standard. The anti-inflammatory activity was evaluated using carrageenan-induced rat paw edema method and indomethacin as the standard. The quantitative structure–activity relationships (QSAR) studies were carried out by correlating, individually, the analgesic activity and the anti-inflammatory activity of the synthesized compounds with their physicochemical descriptors using multiple linear regression method. The predictability of the QSAR model was estimated using internal and external predictivity methods. Most of the synthesized compounds showed significant analgesic and anti-inflammatory activities. Compounds having high molecular weight and electron donating groups showed good analgesic activity. Compounds possessing high molar volume and electron donating substituents showed good anti-inflammatory activity. The compound, 1-(40 -methoxyphenyl)-3-(300-methoxy-400-hydroxyphenyl)-2-propen-1-one, showed higher analgesic activity than the standard, aspirin, as well as higher anti-inflammatory activity than indomethacin.