Ennis, who missed last month's European Indoor Championships in Paris with an ankle tendon injury that prevented her from running for seven weeks, will race over 150 metres and the hurdles on a specially made city-centre track.
The 25-year-old said: "I imagine I'll be quite nervous as it's my first race of the season."
Ennis, who is gearing up for the defence of her world title in Daegu, South Korea, in August, confirmed she will take part in her first heptathlon of the year in Gotzis, Austria, on 28 and 29 May.
The City Games follows the Great Manchester Run in which Paula Radcliffe, in her comeback race following a 15-month absence, and marathon world record holder Haile Gebrselassie will compete.
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