Amide-proton-transfer weighted (APTw) MRI has emerged as a non-invasive pH-weighted imaging technique for studies of several diseases such as ischemic stroke. However, its pH-sensitivity is relatively low, limiting its capability to detect small pH changes. In this work, computer simulations, protamine phantom experiments, and in vivo gas challenge and experimental stroke in rats showed that, with judicious selection of the saturation pulse power, the amide-CEST at 3.6 ppm and guanidyl-CEST signals at 2.0 ppm changed in opposite directions with decreased pH. Thus, the difference between amide-CEST and guanidyl-CEST can enhance the pH measurement sensitivity, and is dubbed as pHenh. Acidification induced a negative contrast in APTw, but a positive contrast in pHenh. In vivo experiments showed that pHenh can detect hypercapnia-induced acidosis with about 3-times higher sensitivity than APTw. Also, pHenh slightly reduced gray and white matter contrast compared to APTw. In stroke animals, the CEST contrast between the ipsilateral ischemic core and contralateral normal tissue was −1.85 ± 0.42% for APTw and 3.04 ± 0.61% (n = 5) for pHenh, and the contrast to noise was 2.9 times higher for pHenh than APTw. Our results suggest that pHenh can be a useful tool for non-invasive pH-weighted imaging.