As opportunities grow for resource-constrained countries to use eHealth (digital health) to strengthen health systems, a dilemma arises. Wise eHealth investments require adequate appraisal to address opportunity costs. Economic appraisal techniques conventionally utilised for this purpose require sufficient economic expertise and adequate data that are frequently in short supply in low- and middle-income countries. This paper aims to identify, and, if required, develop, a suitable framework for performing eHealth investment appraisals in settings of limited economic expertise and data. Four progressive steps were followed: (1) identify required framework attributes from published checklists; (2) select, review, and chart relevant frameworks using a scoping review; (3) analyse the frameworks using deductive and inductive iterations; and, if necessary, (4) develop a new framework using findings from the first three steps. Twenty-four candidate investment appraisal attributes were identified and seven relevant frameworks were selected for review. Analysis of these frameworks led to the refinement of the candidate attributes to 23 final attributes, and each framework was compared against them. No individual framework adequately addressed sufficient attributes. A new framework was developed that addressed all 23 final attributes. A new evidence-based investment appraisal framework has been developed that provides a practical, business case focus for use in resource-constrained African settings.