Ten genetically diverse inbred lines, including two genic male sterile lines, of muskmelon (Cucumis melo L.) were crossed in a half-diallel to generate 45 F1 hybrids. These hybrids, along with the parental lines and commercial check, were evaluated for their fruit yield, level of phytochemicals and Fusarium wilt resistance. Both additive and non-additive genetic variances were important in governing the expression of all of the traits; however, the additive gene action for the fruit weight (g), flesh thickness (cm), rind thickness (mm), firmness (lb inch−2), β-carotene content (mg/100 g), non-additive variance for fruit yield (t ha−1), fruit number, total soluble solids (TSS, °Brix), ascorbic acid (mg/100 g) and reaction to Fusarium wilt were comparatively more important. The parental line MM-625 was the best general combiner for fruit yield, rind thickness and β-carotene content (mg/100 g). The exotic line Riogold was the best combiner for flesh thickness and firmness. The netted inbred line MM-610 was the best general combiner for fruit weight, ascorbic acid and reaction to Fusarium wilt. The inbred lines KP4HM-15 and MM-916 were the best general combiners for the number of fruits per vine and TSS. The best cross-combinations for fruit yield ha−1 and TSS were MS-1×M-610 and Kajri×MM-904, respectively. The hybrids KP4HM-15×MM Sel-103 and KP4HM-15×MM-1831 recorded the highest standard heterosis for fruit yield and TSS. The landrace-derived inbred lines Kajri, MM Sel-103 and KP4HM-15 produced moderate-to-highly FW-resistant hybrids. Out of the 121 SSR markers applied, 70 exhibited parental polymorphism. The markers DM0561, CMAAAGN14, TJ147, CMMS35_3, CMAGN45 and DE1337 identified specific/unique alleles in certain parental genotypes. Thus, the findings of this study revealed that the novel inbred lines can effectively be combined to generate heterotic F1 hybrids for yield and other traits, such as rind and flesh thickness, TSS, β-carotene content and firmness. Furthermore, SSR markers can potentially be utilized to confirm the genetic diversity among the parental lines, and for the DNA fingerprinting of F1 hybrids.