BACKGROUND: Infectious disease surveillance is difficult in many low- and middle-income countries. Information market (IM)-based participatory surveillance is a crowdsourcing method that encourages individuals to actively report health symptoms and observed trends by trading web-based virtual "stocks" with payoffs tied to a future event. OBJECTIVE: This study aims to assess the feasibility and acceptability of a tailored IM surveillance system to monitor population-level COVID-19 outcomes in Accra, Ghana. METHODS: We designed and evaluated a prediction markets IM system from October to December 2021 using a mixed methods study approach. Health care workers and community volunteers aged ≥18 years living in Accra participated in the pilot trading. Participants received 10,000 virtual credits to trade on 12 questions on COVID-19-related outcomes. Payoffs were tied to the cost estimation of new and cumulative cases in the region (Greater Accra) and nationwide (Ghana) at specified future time points. Questions included the number of new COVID-19 cases, the number of people likely to get the COVID-19 vaccination, and the total number of COVID-19 cases in Ghana by the end of the year. Phone credits were awarded based on the tally of virtual credits left and the participant's percentile ranking. Data collected included age, occupation, and trading frequency. In-depth interviews explored the reasons and factors associated with participants' user journey experience, barriers to system use, and willingness to use IM systems in the future. Trading frequency was assessed using trend analysis, and ordinary least squares regression analysis was conducted to determine the factors associated with trading at least once. RESULTS: Of the 105 eligible participants invited, 21 (84%) traded at least once on the platform. Questions estimating the national-level number of COVID-19 cases received 13 to 19 trades, and obtaining COVID-19-related information mainly from television and radio was associated with less likelihood of trading (marginal effect: -0.184). Individuals aged <30 years traded 7.5 times more and earned GH ¢134.1 (US $11.7) more in rewards than those aged >30 years (marginal effect: 0.0135). Implementing the IM surveillance was feasible; all 21 participants who traded found using IM for COVID-19 surveillance acceptable. Active trading by friends with communal discussion and a strong onboarding process facilitated participation. The lack of bidirectional communication on social media and technical difficulties were key barriers. CONCLUSIONS: Using an IM system for disease surveillance is feasible and acceptable in Ghana. This approach shows promise as a cost-effective source of information on disease trends in low- and middle-income countries where surveillance is underdeveloped, but further studies are needed to optimize its use.