Selecting vegetable cultivars suitable to local environmental conditions and with quality traits desired by the evolving market and consumer needs is an important production decision farmers face annually. As seed companies continue to expand their offerings of new cultivars and rootstocks, selecting the best cultivar and/or scion/rootstock combination can be challenging for farmers. Land-grant universities, through their integrated research and extension programs, can provide an unbiased, science-based evaluation of the available cultivar and rootstock options to assist farmers in making this important selection. A two-year study was conducted to evaluate 20 hybrid cultivars and two grafted entries of muskmelons at three locations in Pennsylvania in 2018 and 2019 to provide farmers with science-based recommendations focused on fruit yield and physicochemical quality characteristics. Most cultivars did not differ in fruit yields from the standard “Aphrodite”. “Sugar Cube” produced more, smaller sized melons than “Aphrodite”. However, the combination of the soluble solids concentration, flesh pH, and titratable acidity values was not as favorable, indicating that consumer preference may be lower for “Sugar Cube” than for other cultivars. Yield from grafted entries was not different from the non-grafted “Aphrodite”; although, biotic and abiotic stressors favoring the use of grafting were not present throughout the study. Physicochemical evaluation of the combination of “Aphrodite” scion and “Flexifort” rootstock was more favorable than “Aphrodite/RS841” and non-grafted “Aphrodite”. This combination may be desirable even in the absence of yield stressors.