Following his PhD, Chibale joined the University of Liverpool as a Sir William Ramsay British Postdoctoral Research Fellow. He developed optically active alcohols using lanthanides. In 1994 he joined the Scripps Research Institute, creating complicated natural and designed molecules from organic building blocks. He began to explore angiogenesis inhibitors, which can be used to stop cancer cells developing new blood vessels. Inspired by medicinal chemistry, Chibale returned to Africa in 1996, joining the research group of James Bull. In 2002 he joined the University of California, San Francisco as a Sandler Foundation Sabbatical Fellow. He was promoted to the rank of  Professor in 2007 and a Life Fellow of the University of Cape Town in 2009. His group currently studies treatments for malaria, tuberculosis, and antibiotic-resistant microbial diseases. He set up collaborations and exchange programs for South African students to learn how to translate basic science into potential products. He was elected a Fellow of the Royal Society of South Africa in 2009.
In 2010 he founded H3D, the first drug discovery centre at the University of Cape Town. The research program received significant media attention and has been supported by Bill Gates. In 2008 he took a sabbatical, working as a Fulbright scholar at the University of Pennsylvania and Pfizer. In 2012 Chibales group discovered MMV390048, an aminopyridine compound that can be used as a single-dose treatment for malaria. It was the first antimalarial medicine to enter phase 1 human studies in Africa. In 2016 they discovered another antimalarial compound, UCT943. He has written for The Conversation about how Africas medicinal drug research can paved the landscape for health innovation in the continent.
Today he holds the Neville Isdell Chair in African-centric Drug Discovery and Development at the University of Cape Town. Over the years H3D has partnered with the South African government and innovative pharmaceutical companies to build Africa's capacity for research.
In 2016 the Royal Society of Chemistry recognised him as one of their 175 Faces of chemistry. He was elected a Fellow of the Royal Society of Chemistry in 2014.
Kelly has received many notable awards and honors, which include: 
* a 2010/11 National Science and Technology Forum-BHP Billiton Award in the category TW Kambule NRF Senior Black Researcher (2011)
* UCT Alan Pifer Research Award (2011)
* South African National Research Foundation (NRF) Special Recognition Award: Champion of Research Capacity Development at South African Higher Education Institutions (2012)
* South African Medical Research Council Gold Medal (2016)
* Cheney Visiting Fellowship from the University of Leeds in the UK (2017-2018) 
* South African Chemical Institute Gold Medal (2018)
Kelly was also: 
# [https://newafricanmagazine.com/100/#PharmaPioneer%20#ZambianScientist%20#African one of the 100 Most Influential Africans] by New African magazine for 2019
# one of the world’s top 60 most influential/ inspirational leaders in the pharmaceutical industry on [https://themedicinemaker.com/power-list/2020 The Medicine Maker's 2020] and [https://themedicinemaker.com/power-list/2021/small-molecules/kelly-chibale 2021] Power Lists
# [https://timmermanreport.com/2021/06/on-juneteenth-honoring-22-black-biotech-leaders/ one of the 22 black biotech leaders] in honour of Juneteenth in the USA in 2021. The list, published by the Timmerman Report, celebrates innovative black leaders who are change-makers in their respective fields; 
# [https://harvardpublichealth.org/25-names-to-know-in-african-public-health/ one of the 25 standout voices in African public health] by Harvard University’s Public Health magazine, 12 May 2022 
# the first E[https://axial.acs.org/medicinal-chemistry/kelly-chibale-named-editor-in-chief-of-acs-medicinal-chemistry-letters ditor-In-Chief from Africa of an American Chemical Society] (ACS) publication when appointed EIC of ACS Medicinal Chemistry Letters in 2023
# Awarded [https://www.ch.cam.ac.uk/news/kelly-chibale-recognised-drug-discovery-research Royal Society (UK) Africa Prize] 2023
# Awarded [https://www.schmidtfutures.org/second-cohort-of-ai2050-senior-fellows-named-by-schmidt-futures/ Schmidt Sciences AI2050 Senior Fellowship 2023], one of seven worldwide
# Awarded [https://www.unibas.ch/en/News-Events/News/Uni-People/The-University-of-Basel-is-awarding-Kelly-Chibale-with-an-honory-doctorate.html Honorary Doctorate of the Faculty of Science], University of Basel in 2023