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."

It coincides with the release of figures showing that 24 people died on Scotland's coastline in 2014.
Over the past five years, the average fatality rate in Scotland was 35 each year.
Scotland experiences proportionately more coastal drownings than the UK as a whole. The UK figure for 2014 recorded by the RNLI was 163.
The charity's Respect the Water campaign aims to halve the rate of drownings by 2024.
It includes two films which will be shown in cinemas throughout the UK.
The largest proportion of deaths over the past five years - 24% - were accounted for by people slipping and falling into the water while walking and running.
Other dangers included:
Men are considerably more likely to put themselves in danger than women. Over the five-year period, 74% of those who died were men.
RNLI lifeboat crews in Scotland saved 51 lives in 2014.
The charity has highlighted dangers which can be more common in Scotland.
After falling in, people can experience cold water shock or the effects of strong currents under the surface. There are also problems with slippery rocks, sudden waves or unstable ground.
RNLI coastal safety manager for Scotland Michael Avril said: "We want people to enjoy the water but to make sure they respect it.
"Around 35 lives are lost around Scotland's coast each year but many of these losses could be avoided if people acknowledge the dangers and follow some basic safety advice."
The deputy leader of Sheffield City Council has announced he is to stand down after 13 years as a councillor.
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The RNLI has launched a drowning prevention campaign with the intention of reducing coastal deaths by 50%.