Labour's Leigh Bramall said he was leaving the council to take up a job at a communication company in Sheffield.
He said he remained "100% committed" to the work of the Labour run-authority but added "I have to put my family first".
Council leader Julie Dore paid tribute to Mr Bramall's work saying he had "given his all to the job".
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Mr Bramall, 42, has represented Southey since 2004 and was appointed deputy leader of the council in 2015.
He said: "I have put everything into my job and love what I do.
"But I have to put my family first and now is the right time for me to move on.
"I am moving to a fantastic Sheffield company and feel this is a great opportunity for me to start a new chapter in my professional career which also allows me to stay in Sheffield, the city that I love."
Ms Dore said: "He has been dedicated to serving the people of Sheffield as Deputy Leader of the Council and given his all to the job.
"This inevitably takes its toll on your personal life and I completely understand and respect the decision he has made. I wish him all the best for his future career."
The deputy leader of Sheffield City Council has announced he is to stand down after 13 years as a councillor.